PRC1 inhibitors and methods of treatment therewith

ABSTRACT

Provided herein are small molecule inhibitors of Polycomb Repressive Complex 1 (PRC1) activity, and methods of use thereof for the treatment of disease, including leukemia and other cancers, as well as other diseases dependent on the activity of PRC1.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims the priority benefit of U.S. ProvisionalPatent Application No. 62/681,989, filed Jun. 7, 2018, which isincorporated by reference in its entirety.

FIELD

Provided herein are small molecule inhibitors of Polycomb RepressiveComplex 1 (PRC1) activity, and methods of use thereof for the treatmentof disease, including leukemia and other cancers, cancer stem cells, aswell as other diseases dependent on the activity of PRC1.

BACKGROUND

Emerging evidence shows that recurrence of acute leukemia results fromthe activity of leukemia stem cells (LSCs) (Refs. 1-3; hereinincorporated by reference in their entireties). Leukemic stem cells orleukemia-initiating cells represent a rare population of cells that arecapable of self-renewal, proliferation and differentiation intomalignant blasts. LSCs are much more resistant to chemotherapy whencompared to progenitors or blasts (Refs. 1,2; herein incorporated byreference in their entireties) and new pharmacological agents targetingLSCs are urgently needed. Polycomb repressive complex 1 (PRC1) plays keyrole in regulation of stem cell activity. Compounds inhibiting PRC1activity via blocking RING1B-BMI1 E3 ligase have potential toselectively target leukemia stem cells as well as cancer stem cells ingeneral.

SUMMARY

Provided herein are small molecule inhibitors of Polycomb RepressiveComplex 1 (PRC1) activity, and methods of use thereof for the treatmentof disease, including leukemia and other cancers, as well as otherdiseases dependent on the activity of PRC1.

In some embodiments, PRC1 inhibitors herein comprise a substitutedpyrrole, furan, or thiophene ring. In some embodiments, PRC1 inhibitorsherein comprise Formula (I):

wherein R¹ is an aromatic ring, heteroaromatic ring, substitutedaromatic ring, or substituted heteroaromatic ring; wherein R² is analiphatic group (e.g., straight or branched aliphatic chain, substitutedor unsubstituted, etc.), cycloalkyl, or substituted cycloalkyl; whereinR³ is an aromatic ring, heteroaromatic ring, substituted aromatic ring,or substituted heteroaromatic ring; wherein R⁴ is a carboxylic acid(e.g., COOH, CH₂COOH, etc.), alcohol, tetrazole, ester, amide,sulfonamide, sulfone, phosphonate, heterocycle, etc., or a carboxylicacid bioisostere; wherein X is, NH, NR⁵, O, or S; and wherein R⁵, whenpresent, is straight or branched alkyl (e.g. CH₃), (CH₂)₁₋₆—COOH,(CH₂)₁₋₆—OH, NH₂, cycloalkyl, substituted cycloalkyl, amide. In someembodiments, R1, R2, R3, and R4 are any of the correspondingsubstituents depicted in the compounds of Table A.

In some embodiments, PRC1 inhibitors herein comprise a substitutedpyrrole, furan, or thiophene ring. In some embodiments, PRC1 inhibitorsherein comprise Formula (II):

wherein R² is an aliphatic group (e.g., straight or branched aliphaticchain (e.g. isopropyl, isobuthyl, etc.) substituted or unsubstituted),haloalkyl (e.g. mono-fluoro substituted straight or branched alkyl,di-fluoro substituted straight or branched alkyl, tri-fluoro substitutedstraight or branched alkyl, etc), cycloalkyl (e.g. cyclopropyl,cyclobuthyl, cyclopenthyl, etc.), or substituted cycloalkyl; wherein R⁴is a carboxylic acid (e.g., COOH, (CH₂)₁₋₅COOH, etc.), alcohol (e.g.—OH, (CH₂)₁₋₆OH, etc), tetrazole, ester, amide, —(CH₂)₁₋₅C(O)NH₂,sulfonamide, —(CH₂)₀₋₅SO₂NH₂, —(CH₂)₀₋₅SO₂CH₃, —NHSO₂NH₂, sulfone,phosphonate, heterocycle, etc., or a carboxylic acid bioisostere;wherein X is, NH, NR⁵, O, or S; wherein R⁵, when present, is straight orbranched alkyl (e.g. CH₃), (CH₂)₁₋₆—COOH, (CH₂)₁₋₆—CONH₂,(CH₂)₁₋₆—SO₂NH₂, (CH₂)₁₋₆—OH, NH₂, substituted alkyl, heteroalkyl,substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, amide;wherein A, A′, E, and E′ are independently selected from cycloalkyl,heteroalkyl, heterocycloalkyl, aryl, and heteroaryl rings (e.g., ringsof Table 1, phenyl ring, etc.) that are linked to form any suitablebicyclic ring systems (AA′ and EE′), such as the bicyclic ring systemsof Table 2, any suitable tricyclic rings made by combining a ring ofTable 1 (or phenyl ring) with a bicyclic ring of Table 2); whereinR^(A1-5), R^(A′1-5), R^(E1-5), and R^(E′1-5) may be absent or present,may be located at any position on the bicyclic ring system, may bepresent simultaneously at more than one position, and when present isselected from C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈branched alkyl (e.g. isopropyl, isobuthyl, etc.), substituted alkyl,haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc), C₁-C₈ alkoxy (e.g.methoxy, ethoxy, etc.), —OCF₃, —OH, —(CH₂)₁₋₆OH, ether (e.g.—(CH₂)₁₋₅O(CH₂)₁₋₅—CH₃, etc.), —OR⁶, —(CH₂)₁₋₆OR⁶, amide (e.g.—(CH₂)₀₋₆CONH₂), substituted amide (e.g. —(CH₂)₀₋₅NHCOR⁶ (e.g. compounds176-180), —(CH₂)₀₋₅CONHR⁶ (e.g. compounds 198-200)), —NH₂, substitutedamine (—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶, carboxy (e.g.—(CH₂)₀₋₆COOH), sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substitutedsulfonamide (e.g. —(CH₂)₀₋₆SO₂NHR⁶), —(CH₂)₀₋₆SO₂CH₃, —(CH₂)₀₋₆SO₂CH₂R⁶,—NHSO₂NH₂, —NHSO₂NHR⁶, —NHSO₂CH₂R⁶, sulphone, phosphonate, —SH, —CN,halogen, heteroalkyl, substituted heteroalkyl, aryl, heteroaryl (e.g.tetrazole, triazole, isoxazole, thiadiazole, pyrazole, thiophene, etc.)or any suitable ring of Table 1; wherein R⁶, when present, is C₁-C₈alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈ branched alkyl (e.g.isopropyl, isobuthyl, etc.), alkyne, alkene, substituted alkyl,haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc), C₁-C₈ alkoxy,—(CH₂)₁₋₆OH, ether (e.g. —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.), amide (e.g.—(CH₂)₁₋₆CONH₂), amine, substituted amine, heteroalkyl, C₃-C₈ saturatednon-aromatic ring substituted or non-substituted, C₃-C₈ heterocyclicsaturated ring, aryl (e.g. phenyl), heteroaryl (e.g. tetrazole,triazole, isoxazole, thiadiazole, pyrazole, thiophene, pyridine, indole,etc.) or any suitable ring of Table 1, etc.

In some embodiments, PRC1 inhibitors herein comprise a substitutedpyrrole, furan, or thiophene ring. In some embodiments, PRC1 inhibitorsherein comprise Formula (III):

wherein R² is an aliphatic group (e.g., straight or branched aliphaticchain (e.g. isopropyl, isobuthyl, etc.) substituted or unsubstituted),haloalkyl (e.g. mono-fluoro substituted straight or branched alkyl,di-fluoro substituted straight or branched alkyl, tri-fluoro substitutedstraight or branched alkyl, etc), cycloalkyl (e.g. cyclopropyl,cyclobuthyl, cyclopenthyl, etc.), or substituted cycloalkyl; wherein R⁴is a carboxylic acid (e.g., COOH, (CH₂)₁₋₅COOH, etc.), alcohol (e.g.—OH, (CH₂)₁₋₆OH, etc), tetrazole, ester, amide, —(CH₂)₁₋₅C(O)NH₂,sulfonamide, —(CH₂)₀₋₅SO₂NH₂, —(CH₂)₀₋₅SO₂CH₃, —NHSO₂NH₂, sulfone,phosphonate, heterocycle, etc., or a carboxylic acid bioisostere;wherein X is, NH, NR⁵, O, or S; wherein R⁵, when present, is straight orbranched alkyl (e.g. CH₃), (CH₂)₁₋₆—COOH, (CH₂)₁₋₆—CONH₂,(CH₂)₁₋₆—SO₂NH₂, (CH₂)₁₋₆—OH, NH₂, substituted alkyl, heteroalkyl,substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, amide;wherein R^(A1-3), R^(A′1-3), R^(E1-3), and R^(E′1-3) may be absent orpresent, may be located at any position on the bicyclic ring system, maybe present simultaneously at more than one position, and when present isselected from C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈branched alkyl (e.g. isopropyl, isobuthyl, etc.), substituted alkyl,haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc), C₁-C₈ alkoxy (e.g.methoxy, ethoxy, etc.), —OCF₃, —OH, —(CH₂)₁₋₆OH, ether (e.g.—(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.), —OR⁶, —(CH₂)₁₋₆OR⁶, amide (e.g.—(CH₂)₀₋₆CONH₂), substituted amide (e.g. —(CH₂)₀₋₅NHCOR⁶ (e.g. compounds176-180), —(CH₂)₀₋₅CONHR⁶ (e.g. compounds 198-200)) —NH₂, substitutedamine (—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶, carboxy (e.g.—(CH₂)₀₋₆COOH), sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substitutedsulfonamide (e.g. —(CH₂)₀₋₆SO₂NHR⁶), —(CH₂)₀₋₆SO₂CH₃, —(CH₂)₀₋₆SO₂CH₂R⁶,—NHSO₂NH₂, —NHSO₂NHR⁶, —NHSO₂CH₃, —NHSO₂CH₂R⁶, sulphone, phosphonate,—SH, —CN, halogen, heteroalkyl, substituted heteroalkyl, aryl,heteroaryl (e.g. tetrazole, triazole, isoxazole, thiadiazole, pyrazole,thiophene, etc.) or any suitable ring of Table 1; wherein R⁶, whenpresent, is C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈branched alkyl (e.g. isopropyl, isobuthyl, etc.), alkyne, alkene,substituted alkyl, haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc),C₁-C₈ alkoxy, —(CH₂)₁₋₆OH, ether (e.g. —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.),amide (e.g. —(CH₂)₁₋₆CONH₂), amine, substituted amine, heteroalkyl,C₃-C₈ saturated non-aromatic ring substituted or non-substituted, C₃-C₈heterocyclic saturated ring, aryl (e.g. phenyl), heteroaryl (e.g.tetrazole, triazole, isoxazole, thiadiazole, pyrazole, thiophene,pyridine, indole, etc.) or any suitable ring of Table 1, etc.; whereinA¹⁻³ and E¹⁻³ are independently selected from CH₂, CH, NH, N, O and S(e.g., wherein two each of A¹⁻³ and/or E¹⁻³ are independently CH₂ or CHand one is NH, N, O, or S; wherein one each of A¹⁻³ and/or E¹⁻³ areindependently CH₂ or CH and two are NH, N, O, or S; etc.) wherein E⁴ isselected from CH or N. In some embodiments, the 5-member portions of theA and E ring systems is aromatic (e.g., comprises one or more doublebonds to result in aromaticity of the ring). In some embodiments, the5-member portions of the A and E ring systems are independently selectedfrom saturated 5-membered rings or aromatic 5-member rings.

In some embodiments, R¹ comprises an aromatic ring (or ring system(e.g., indole, phenyl, pyrdine, purine, etc.)). In some embodiments, R¹comprises an aromatic ring selected from the group consisting of furan,pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,benzene, pyridine, pyrazine, pyrimadine, pyridazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, benzofuran, isobenzofuran, indole,isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole,benzisoxazole, benzothiozole, napthalene, anthracene, quinoline,isoquinoline, quinoxaline, acridine, quinazoline, cinnoline,phthalazine, etc.

In some embodiments, the aromatic ring at R¹ is linked to the core ring(e.g., furan, pyrrole, or thiophene) of Formula (I) at any suitableposition on the aromatic ring. In some embodiments, the aromatic ring atR¹ is directly linked (e.g., by a single covalent bond) to the core ring(e.g., furan, pyrrole, or thiophene) of Formula (I). In someembodiments, the aromatic ring at R¹ is linked to the core ring (e.g.,furan, pyrrole, or thiophene) of Formula (I) by a linker moiety.Suitable linkers include 0-3 linearly connected C, S, O, and/or Nmembers, wherein any C or N members of the linker may be optionallysubstituted with any suitable substituent, such as CH₃, CH₂CH₃, CH═CH₂,OH, CH₂OH, OCH₃, NH₂, CH₂NH₂, NHCH₃, NO₂, SH, CH₂SH, SCH₃, Cl, Br, F, I,CH₂Cl, CH₂Br, CH₂F, CH₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃,CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, CH₂COOH, CONH₂,CH₂CONH₂, and combinations thereof. In some embodiments, R¹ comprises asubstituted aromatic ring. Any of the aforementioned R¹ aromatic ringsmay be substituted at one or more positions (e.g., 2, 3, 4, 5, 6, ormore, depending upon the size of the ring or ring system). In someembodiments, a substituent of an R¹ aromatic ring is selected from thegroup consisting of CH₃, (CH₂)₁₋₆CH₃, CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH,(CH₂)₁₋₄OH, OCH₃, OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₄NH₂, NHCH₂CH₃, NHCH₃,NO₂, CH₂NHCH₃, (CH₂)₁₋₄NH(CH₂)₁₋₆CH₃, (CH₂)₁₋₆O(CH₂)₁₋₄CH₃,(CH₂)₁₋₆S(CH₂)₁₋₆CH₃. SH, (CH₂)₁₋₄SH, SCH₃, CH₂SCH₃, Cl, Br, F, I,(CH₂)₁₋₂Cl, (CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CF₂H, CFH₂, CBr₃,CCl₃, CI₃, CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH,(CH₂)₁₋₄COOH, CONH₂, (CH₂)₁₋₄CONH₂, (CH₂)₁₋₄X(CH₃), (CH₂)₁₋₆X(CH₂)₁₋₆CH₃where is X═O, NH, S, tetrazole, triazole, isoxazole, thiadiazole,pyrazole, thiophene, pyridine, indole, sulfonamide (e.g.—(CH₂)₀₋₆SO₂NH₂), substituted sulfonamide, —(CH₂)₀₋₆SO₂CH₃, —NHSO₂NH₂,—NHSO₂CH₃, sulphone, phosphonate, —(CH₂)₀₋₆CONH₂, substituted amide—(CH₂)₀₋₅NHCOR⁶, substituted amine (—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶,carboxy (e.g. —(CH₂)₀₋₆COOH), sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂),substituted sulfonamide, —(CH₂)₀₋₆SO₂CH₃. —NHSO₂NH₂, —NHSO₂CH₃,sulphone, phosphonate and combinations thereof; wherein R⁶, whenpresent, is C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈branched alkyl (e.g. isopropyl, isobuthyl, etc.), alkyne, alkene,substituted alkyl, haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc),C₁-C₈ alkoxy, —(CH₂)₁₋₆OH, ether (e.g. —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.),amide (e.g. —(CH₂)₁₋₆CONH₂), amine, substituted amine, heteroalkyl,C₃-C₈ saturated non-aromatic ring substituted or non-substituted, C₃-C₈heterocyclic saturated ring, aryl (e.g. phenyl), heteroaryl (e.g.tetrazole, triazole, isoxazole, thiadiazole, pyrazole, thiophene,pyridine, indole, etc.) or any suitable ring of Table 1, etc.

In some embodiments, an R¹ aromatic ring comprises two or moresubstituents selected from the group consisting of CH₃, (CH₂)₁₋₂CH₃,CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₄OH, OCH₃, OCH₂CH₃, CH₂OCH₃,NH₂, (CH₂)₁₋₄NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, (CH₂)₁₋₄NH(CH₂)₁₋₆CH₃,(CH₂)₁₋₆O(CH₂)₁₋₄CH₃, (CH₂)₁₋₆S(CH₂)₁₋₆CH₃. SH, (CH₂)₁₋₄SH, SCH₃,CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I,CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃,CH₂CCl₃, CH₂CI₃, CN, COOH, (CH₂)₁₋₆COOH, CONH₂, (CH₂)₁₋₄CONH₂,(CH₂)₁₋₄X(CH₃)(CH₂)₁₋₄X(CH₂)₁₋₄CH₃ where is X═O, NH, S, tetrazole,triazole, isoxazole, thiadiazole, pyrazole, thiophene, pyridine, indole,sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substituted sulfonamide,—(CH₂)₀₋₆SO₂CH₃. —NHSO₂NH₂, —NHSO₂CH₃, sulphone, phosphonate,—(CH₂)₀₋₆CONH₂, substituted amide —(CH₂)₀₋₅NHCOR⁶, substituted amine(—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶, carboxy (e.g. —(CH₂)₀₋₆COOH),sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substituted sulfonamide,—(CH₂)₀₋₆SO₂CH₃. —NHSO₂NH₂, —NHSO₂CH₃, sulphone, phosphonate, andcombinations thereof; wherein R⁶, when present, is C₁-C₈ alkyl (e.g.methyl, ethyl, propyl, etc.), C₁-C₈ branched alkyl (e.g. isopropyl,isobuthyl, etc.), alkyne, alkene, substituted alkyl, haloalkyl (e.g.fluoro substituted alkyl, —CF₃, etc), C₁-C₈ alkoxy, —(CH₂)₁₋₆OH, ether(e.g. —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.), amide (e.g. —(CH₂)₁₋₆CONH₂), amine,substituted amine, heteroalkyl, C₃-C₈ saturated non-aromatic ringsubstituted or non-substituted, C₃-C₈ heterocyclic saturated ring, aryl(e.g. phenyl), heteroaryl (e.g. tetrazole, triazole, isoxazole,thiadiazole, pyrazole, thiophene, pyridine, indole, etc.) or anysuitable ring of Table 1, etc. In other embodiments, a substituent of anR¹ aromatic ring selected from the group consisting of alkyl₁₋₁₅,alkenyl₁₋₆, alkynyl₁₋₆, (CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH,(CH₂)₀₋₆C(O)NH(CH₂)₁₋₆, (CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl,sulfonamide, alkylsulfonamide, (CH₂)₀₋₆C(S)NH(CH₂)₁₋₆,(CH₂)₀₋₆O(CH₂)₁₋₆, (CH₂)₀₋₆OH, (CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH,(CH₂)₀₋₆NH(CH₂)₁₋₆, (CH₂)₀₋₆N(CH₂)—(CH₂)₁₋₆, (CH₂)₀₋₆NH₂,(CH₂)₀₋₆SO₂(CH₂)₁₋₆, (CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen(e.g., F, Cl, Br, or I), haloalkyl (e.g., (CH₂)₀₋₆ CH₂F,(CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), dihaloalkyl(e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃ CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl,or I), trihaloalkyl (e.g., (CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I),alkyl with 1-3 halogens at two or more positions along its length,(CH₂)₁₋₄SP(Ph)₂═S, (CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₄NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₃C(O)O(CH₂)₀₋₃, (CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃,(CH₂)₀₋₃C(S)S(CH₂)₀₋₃, (CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, and (CH₂O)₁₄.

In some embodiments, R² is an aliphatic group (e.g., straight orbranched aliphatic chain, substituted or unsubstituted, etc.),cycloalkyl, or substituted cycloalkyl (e.g. cyclopropyl, cyclobuthyl,cyclopenthyl, etc.), haloalkyl (e.g. mono-fluoro substituted straight orbranched alkyl, di-fluoro substituted straight or branched alkyl,tri-fluoro substituted straight or branched alkyl, etc), In someembodiments, R² is an aliphatic group comprising any suitablecombination of 1-20 connected carbon atoms (e.g., connected by single,double, and/or triple bonds) and the requisite H (or D) atoms. In someembodiments, R² comprises an aliphatic group selected from methane,acetylene, ethylene, ethane, propyne, propene, propane, isopropane,1,2-butadiene, 1-butyne, 1-butene, butane, isobutane, cyclopropane,cyclobutane, cyclopentane, cyclohexene, n-pentane, cycloheptane,methylcyclohexane, cubane, nonane, dicyclopentadiene, phellandrene,α-terpinene, limonene, undecane, squalene, polyethylene, etc.

In some embodiments, R² comprises a straight or branched aliphaticchain. In some embodiments, R² comprises a straight or branchedaliphatic chain comprising any suitable combination of 1-20 connectedcarbon atoms (e.g., connected by single, double, and/or triple bonds)and the requisite H (or D) atoms. Exemplary R² aliphatic chains includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, and longer (e.g., pentyl, hexyl, heptyl, octyl, nonyl,decyl, etc.) straight and/or branched (e.g., single branch, multiplebranches) aliphatic chains. In some embodiments, R² aliphatic chainscomprise with comprise one or more halogens (e.g., CL, Br, I, or F inplace of a H) or halogen containing groups (e.g., monohalogenated,dihalogenated, trihalogenated); suitable halogen containing groupsinclude: Cl, Br, F, I, CH₂Cl, CH₂Br, CH₂F, CH₂I, CHCl₂, CHBr₂, CHF₂,CHI₂, CCl₃, CBr₃, CF₃, and CI₃, which may comprise or be attached to anycarbon position of an R² aliphatic chain.

In some embodiments, R² comprises a cycloalkyl group. In someembodiments, R² comprises a cycloalkyl group selected fromcyclorpropane, cyclorpropene cyclobutane, cyclobutene, cyclopentane,cyclopentene, cycleohexane, cycleohexene, and larger cycloalkyl rings(e.g., pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), eithersaturated or comprising one or more double or triple bonds. In someembodiments, R₂ comprises an aliphatic ring system (e.g., two or morefused aliphatic rings (e.g., dicyclopentadiene)). In some embodiments, acycloalkyl or substituted cycloalkyl at R² is linked to the core ring(e.g., furan, pyrrole, or thiophene) at any suitable position on thearomatic ring. In some embodiments, the aliphatic ring at R² is directlylinked (e.g., by a single covalent bond) to the core ring (e.g., furan,pyrrole, or thiophene). In some embodiments, the aliphatic ring at R² islinked to the core ring (e.g., furan, pyrrole, or thiophene) by a linkermoiety. Suitable linkers include 0-3 linearly connected C, S, O, and/orN members, wherein any C or N members of the linker may be optionallysubstituted with any suitable substituent, such as CH₃, CH₂CH₃, CH═CH₂,OH, CH₂OH, OCH₃, NH₂, CH₂NH₂, NHCH₃, NO₂, SH, CH₂SH, SCH₃, Cl, Br, F, I,CH₂CI, CH₂Br, CH₂F, CH₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃,CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, CH₂COOH, CONH₂,CH₂CONH₂, and combinations thereof.

In some embodiments, R² comprises a substituted aliphatic ring. Any ofthe aforementioned R² aliphatic rings may be substituted at one or morepositions (e.g., 2, 3, 4, 5, 6, or more, depending upon the size of thering or ring system). In some embodiments, an substituent of an R²aliphatic ring selected from the group consisting of CH₃, (CH₂)₁₋₂CH₃,CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₂OH, OCH₃, OCH₂CH₃, CH₂OCH₃,NH₂, (CH₂)₁₋₂NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, SH, (CH₂)₁₋₂SH, SCH₃,CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I,CF₃, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, andcombinations thereof. In some embodiments, an R² aliphatic ringcomprises two or more substituents selected from the group consisting ofCH₃, (CH₂)₁₋₂CH₃, CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₂OH, OCH₃,OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₂NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, SH,(CH₂)₁₋₂SH, SCH₃, CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br,(CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CBr₃, CH₂CCl₃,CH₂CI₃, CN, and combinations thereof.

In some embodiments, an R¹ aromatic ring comprises two or moresubstituents selected from the group consisting of CH₃, (CH₂)₁₋₂CH₃,CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₆OH, OCH₃, OCH₂CH₃, CH₂OCH₃,NH₂, (CH₂)₁₋₄NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, (CH₂)₁₋₄NH(CH₂)₁₋₆CH₃,(CH₂)₁₋₆O(CH₂)₁₋₄CH₃, (CH₂)₁₋₆S(CH₂)₁₋₆CH₃. SH, (CH₂)₁₋₆SH, SCH₃,CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I,CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃,CH₂CCl₃, CH₂CI₃, CN, COOH, (CH₂)₁₋₆COOH, CONH₂, (CH₂)₁₋₆CONH₂,(CH₂)₁₋₄X(CH₃)(CH₂)₁₋₆X(CH₂)₁₋₆CH₃ where is X═O, NH, S, tetrazole,triazole, isoxazole, thiadiazole, pyrazole, thiophene, pyridine, indole,sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substituted sulfonamide,—(CH₂)₀₋₆SO₂CH₃. —NHSO₂NH₂, —NHSO₂CH₃, sulphone, phosphonate,—(CH₂)₀₋₆CONH₂, substituted amide —(CH₂)₀₋₅NHCOR⁶, substituted amine(—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶, carboxy (e.g. —(CH₂)₀₋₆COOH),sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substituted sulfonamide,—(CH₂)₀₋₆SO₂CH₃. —NHSO₂NH₂, —NHSO₂CH₃, sulphone, phosphonate, andcombinations thereof; wherein R⁶, when present, is C₁-C₈ alkyl (e.g.methyl, ethyl, propyl, etc.), C₁-C₈ branched alkyl (e.g. isopropyl,isobuthyl, etc.), alkyne, alkene, substituted alkyl, haloalkyl (e.g.fluoro substituted alkyl, —CF₃, etc), C₁-C₈ alkoxy, —(CH₂)₁₋₆OH, ether(e.g. —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.), amide (e.g. —(CH₂)₁₋₆CONH₂), amine,substituted amine, heteroalkyl, C₃-C₈ saturated non-aromatic ringsubstituted or non-substituted, C₃-C₈ heterocyclic saturated ring, aryl(e.g. phenyl), heteroaryl (e.g. tetrazole, triazole, isoxazole,thiadiazole, pyrazole, thiophene, pyridine, indole, etc.), etc. In otherembodiments, a substituent of an R¹ aromatic ring selected from thegroup consisting of alkyl₁₋₁₅, alkenyl₁₋₆, alkynyl₁₋₆, (CH₂)₀₋₆C(S)NH₂,(CH₂)₀₋₆C(O)NH₂, O, S, NH, (CH₂)₀₋₆C(O)NH(CH₂)₁₋₆,(CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl, sulfonamide, alkylsulfonamide,(CH₂)₀₋₆C(S)NH(CH₂)₁₋₆, (CH₂)₀₋₆O(CH₂)₁₋₆, (CH₂)₀₋₆OH,(CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH, (CH₂)₀₋₆NH(CH₂)₁₋₆,(CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆, (CH₂ (CH₂)₀₋₆NH₂, (CH₂)₀₋₆SO₂(CH₂)₁₋₆,(CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen (e.g., F, Cl, Br, or I),haloalkyl (e.g., (CH₂)₀₋₆ CH₂F, (CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar withBr, Cl, or I), dihaloalkyl (e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), trihaloalkyl (e.g.,(CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I), alkyl with 1-3 halogens attwo or more positions along its length, (CH₂)₁₋₄SP(Ph)₂═S,(CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₁₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₄NH(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₃C(O)O(CH₂)₀₋₃,(CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃, (CH₂)₀₋₃C(S)S(CH₂)₀₋₃,(CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, and (CH₂O)₁₋₆.

In some embodiments, the aromatic ring at R³ is linked to the core ring(e.g., furan, pyrrole, or thiophene) of Formula (I) at any suitableposition on the aromatic ring. In some embodiments, the aromatic ring atR³ is directly linked (e.g., by a single covalent bond) to the core ring(e.g., furan, pyrrole, or thiophene) of Formula (I). In someembodiments, the aromatic ring at R³ is linked to the core ring (e.g.,furan, pyrrole, or thiophene) of Formula (I) by a linker moiety.Suitable linkers include 0-3 linearly connected C, S, O, and/or Nmembers, wherein any C or N members of the linker may be optionallysubstituted with any suitable substituent, such as CH₃, CH₂CH₃, CH═CH₂,OH, CH₂OH, OCH₃, NH₂, CH₂NH₂, NHCH₃, NO₂, SH, CH₂SH, SCH₃, Cl, Br, F, I,CH₂Cl, CH₂Br, CH₂F, CH₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃,CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, CH₂COOH, CONH₂,CH₂CONH₂, and combinations thereof. In some embodiments, R³ comprises asubstituted aromatic ring. Any of the aforementioned R³ aromatic ringsmay be substituted at one or more positions (e.g., 2, 3, 4, 5, 6, ormore, depending upon the size of the ring or ring system). In someembodiments, a substituent of an R³ aromatic ring is selected from thegroup consisting of CH₃, (CH₂)₁₋₆CH₃, CH—CH₂, CH═CHCH₃, CH₂CH═CH₂, OH,(CH₂)₁₋₆OH, OCH₃, OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₄NH₂, NHCH₂CH₃, NHCH₃,NO₂, CH₂NHCH₃, SH, (CH₂)₁₋₆SH, SCH₃, CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl,(CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃,CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH,(CH₂)₁₋₆COOH, CONH₂, (CH₂)₁₋₆CONH₂, (CH₂)₁₋₆X(CH₃) where is X═O, NH, S,and combinations thereof. In some embodiments, an R³ aromatic ringcomprises two or more substituents selected from the group consisting ofCH₃, (CH₂)₁₋₂CH₃, CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₄OH, OCH₃,OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₄NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, SH,(CH₂)₁₋₄SH, SCH₃, CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br,(CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CF₂H,CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, (CH₂)₁₋₆COOH, CONH₂,(CH₂)₁₋₆CONH₂, (CH₂)₁₋₄X(CH₃) where is X═O, NH, S, and combinationsthereof. In other embodiments, a substituent of an R³ aromatic ringselected from the group consisting of alkyl₁₋₁₅, alkenyl₁₋₆, alkynyl₁₋₆,(CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH, (CH₂)₀₋₆C(O)NH(CH₂)₁₋₆,(CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl, sulfonamide, alkylsulfonamide,(CH₂)₀₋₆C(S)NH(CH₂)₁₋₆, (CH₂)₀₋₆O(CH₂)₁₋₆, (CH₂)₀₋₆OH,(CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH, (CH₂)₀₋₆NH(CH₂)₁₋₆,(CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆, (CH₂)₀₋₆NH₂, (CH₂)₀₋₆SO₂(CH₂)₁₋₆,(CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen (e.g., F, Cl, Br, or I),haloalkyl (e.g., (CH₂)₀₋₆ CH₂F, (CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar withBr, Cl, or I), dihaloalkyl (e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), trihaloalkyl (e.g.,(CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I), alkyl with 1-3 halogens attwo or more positions along its length, (CH₂)₁₋₆SP(Ph)₂═S,(CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₃C(O)O(CH₂)₀₋₃,(CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃, (CH₂)₀₋₃C(S)S(CH₂)₀₋₃,(CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, and (CH₂O)₁₄.

In some embodiments, R⁴ is a carboxylic acid (e.g., COOH, (CH₂)₁₋₅COOH),alcohol (e.g., (CH₂)₁₋₅H), tetrazole, ester, amide, —(CH₂)₁₋₅CONH₂,heterocycle (e.g. one of the heterocycles listed below), sulfone,sulfonamide, phosphonate, —(CH₂)₀₋₅SO₂NH², —(CH₂)₀₋₅SO₂CH₃, —NHSO₂NH₂,or a carboxylic acid bioisostere. In some embodiments, R⁴ is acarboxylic acid bioisostere, such as:

and the like.

In some embodiments, X is, NH, NR⁵, O, or S; and wherein R⁵, whenpresent, is, CH₂OH, —(CH₂)₁₋₆—COOH, CH₂SH, CH₃, CH₂CH₃, NH₂, CH₂NH₂,CH₂CN, (CH₂)₁₋₆—OH, (CH₂)₁₋₆—CONH₂, (CH₂)₁₋₆—SO₂NH₂, NH₂, cycloalkyl,substituted cycloalkyl, substituted alkyl, heteroalkyl, substitutedheteroalkyl, amide. In some embodiments, A, A′, E, and E′ areindependently selected from phenyl or the rings of Table 1. In someembodiments, A, A′, E, and E′ are independently selected from thebicyclic rings of Table 2 (e.g., one of A and A′ is bicyclic and theother is monocyclic, forming a tricyclic ring system; both A and A′ arebicyclic, forming a tetracyclic ring system; one of E and E′ is bicyclicand the other is monocyclic, forming a tricyclic ring system; both E andE′ are bicyclic, forming a tetracyclic ring system; etc.).

TABLE 1 Exemplary rings

In some embodiments, AA′ and EE′ are independently selected from therings of Table 2.

TABLE 2 Exemplary bicyclic ring systems

In some embodiments, each of R^(A1-5) (R^(A1), R^(A2), R^(A3), R^(A4),and R^(A5)), R^(A′1-5) (R^(A′1), R^(A′2), R^(A′3), R^(A′4), andR^(A′5)), R^(E1-5) (R^(E1), R^(E2), R^(E3), R^(E4), and R^(E5)), andR^(E′1-5) (R^(E′1), R^(E′2), R^(E′3), R^(E′4), and R^(E′5)) areindependently selected from any suitable substituent, such as CH₃,CH₂CH₃, CH═CH₂, OH, CH₂OH, OCH₃, NH₂, CH₂NH₂, NHCH₃, NO₂, CH₂NHCH₃,(CH₂)₁₋₄NH(CH₂)₁₋₆CH₃, (CH₂)₁₋₆O(CH₂)₁₋₆CH₃, (CH₂)₁₋₆S(CH₂)₁₋₆CH₃. SH,CH₂SH, SCH₃, Cl, Br, F, I, CH₂Cl, CH₂Br, CH₂F, CH₂I, CF₃, CF₂H, CFH₂,CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN,COOH, CH₂COOH, CONH₂, CH₂CONH₂, (CH₂)₁₋₄CONH₂, (CH₂)₁₋₄X(CH₃),(CH₂)₁₋₄X(CH₂)₁₋₆CH₃ where is X═O, NH, S, tetrazole, triazole,isoxazole, thiadiazole, pyrazole, thiophene, pyridine, indole,sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substituted sulfonamide (e.g.—(CH₂)₀₋₆SO₂NHR⁶), —(CH₂)₀₋₆SO₂CH₃. —(CH₂)₀₋₆SO₂CH₂R⁶, —NHSO₂NH₂,—NHSO₂NHR⁶, —NHSO₂CH₃, —NHSO₂CH₂R⁶, sulphone, phosphonate,—(CH₂)₀₋₆CONH₂, substituted amide —(CH₂)₀₋₅NHCOR⁶, substituted amine(—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶, carboxy (e.g. —(CH₂)₀₋₆COOH),sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substituted sulfonamide,—(CH₂)₀₋₆SO₂CH₃. —NHSO₂NH₂, —NHSO₂CH₃, and combinations thereof; whereinR⁶, when present, is C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.),C₁-C₈ branched alkyl (e.g. isopropyl, isobuthyl, etc.), alkyne, alkene,substituted alkyl, haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc),C₁-C₈ alkoxy, —(CH₂)₁₋₆OH, ether (e.g. —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.),amide (e.g. —(CH₂)₁₋₆CONH₂), amine, substituted amine, heteroalkyl,C₃-C₈ saturated non-aromatic ring substituted or non-substituted, C₃-C₈heterocyclic saturated ring, aryl (e.g. phenyl), heteroaryl (e.g.tetrazole, triazole, isoxazole, thiadiazole, pyrazole, thiophene,pyridine, indole, etc.), etc. In some embodiments, each of R^(A1-5)(R^(A1), R^(A2), R^(A3), R^(A4), and R^(A5)), R^(A′1-5) (R^(A′1),R^(A′2), R^(A′3), R^(A′4), and R^(A′5)), R^(E1-5) (R^(E1), R^(E2),R^(E3), R^(E4), and R^(E5)), and R^(E′1-5) (R^(E′1), R^(E′2), R^(E′3),R^(E′4), and R^(E′5)) are independently selected from is selected fromthe group consisting of CH₃, (CH₂)₁₋₆CH₃, CH═CH₂, CH═CHCH₃, CH₂CH═CH₂,OH, (CH₂)₁₋₄OH, OCH₃, OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₄NH₂, NHCH₂CH₃,NHCH₃, NO₂, CH₂NHCH₃, (CH₂)₁₋₆NH(CH₂)₁₋₆CH₃, (CH₂)₁₋₆O(CH₂)₁₋₄CH₃,(CH₂)₁₋₆S(CH₂)₁₋₆CH₃, CH₂NHCH₃, SH, (CH₂)₁₋₆SH, SCH₃, CH₂SCH₃, Cl, Br,F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CF₂H, CFH₂,CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN,COOH, (CH₂)₁₋₆COOH, CONH₂, (CH₂)₁₋₄CONH₂, (CH₂)₁₋₄X(CH₃) where is X═O,NH, S, (CH₂)₁₋₄CONH₂, (CH₂)₁₋₆X(CH₃), (CH₂)₁₋₆X(CH₂)₁₋₆CH₃ where is X═O,NH, S, tetrazole, triazole, isoxazole, thiadiazole, pyrazole, thiophene,pyridine, indole, sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substitutedsulfonamide, —(CH₂)₀₋₆SO₂CH₃. —NHSO₂NH₂, —NHSO₂CH₃, sulphone,phosphonate, —(CH₂)₀₋₆CONH₂, substituted amide —(CH₂)₀₋₅NHCOR⁶,substituted amine (—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶, carboxy (e.g.—(CH₂)₀₋₆COOH), sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substitutedsulfonamide, —(CH₂)₀₋₆SO₂CH₃. —NHSO₂NH₂, —NHSO₂CH₃, and combinationsthereof; wherein R⁶, when present, is C₁-C₈ alkyl (e.g. methyl, ethyl,propyl, etc.), C₁-C₈ branched alkyl (e.g. isopropyl, isobuthyl, etc.),alkyne, alkene, substituted alkyl, haloalkyl (e.g. fluoro substitutedalkyl, —CF₃, etc), C₁-C₈ alkoxy, —(CH₂)₁₋₆OH, ether (e.g.—(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.), amide (e.g. —(CH₂)₁₋₆CONH₂), amine,substituted amine, heteroalkyl, C₃-C₈ saturated non-aromatic ringsubstituted or non-substituted, C₃-C₈ heterocyclic saturated ring, aryl(e.g. phenyl), heteroaryl (e.g. tetrazole, triazole, isoxazole,thiadiazole, pyrazole, thiophene, pyridine, indole, etc.), or anysuitable ring of Table 1, etc. In some embodiments, each of R^(A1-5)(R^(A1), R^(A2), R^(A3), R^(A4), and R^(A5)), R^(A′1-5) (R^(A′1),R^(A′2), R^(A′3), R^(A′4), and R^(A′5)), R^(E1-5) (R^(E1), R^(E2),R^(E3), R^(A4), and R^(E5)), and R^(E′1-5) (R^(E′1), R^(E′2), R^(E′3),R^(E′4), and R^(E′5)) are independently selected from is selected fromthe group consisting of alkyl₁₋₁₅, alkenyl₁₋₆, alkynyl₁₋₆,(CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH, (CH₂)₀₋₆C(O)NH(CH₂)₁₋₆,(CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl, sulfonamide, alkylsulfonamide,(CH₂)₀₋₆C(S)NH(CH₂)₁₋₆, (CH₂)₀₋₆O(CH₂)₁₋₆, (CH₂)₀₋₆ H,(CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH, (CH₂)₀₋₆NH(CH₂)₁₋₆,(CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆, (CH₂)₀₋₆NH₂, (CH₂)₀₋₆SO₂(CH₂)₁₋₆,(CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen (e.g., F, Cl, Br, or I),haloalkyl (e.g., (CH₂)₀₋₆ CH₂F, (CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar withBr, Cl, or I), dihaloalkyl (e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), trihaloalkyl (e.g.,(CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I), alkyl with 1-3 halogens attwo or more positions along its length, (CH₂)₁₋₆SP(Ph)₂═S,(CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₆OH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₃C(O)O(CH₂)₀₋₃,(CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃, (CH₂)₀₋₃C(S)S(CH₂)₀₋₃,(CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, and (CH₂O)₁₋₆.

In some embodiments, the substituents R¹—R⁵ and R^(A1-5), R^(A′1-5),R^(E1-5), R^(E′1-5), or linkers are selected from any of thesubstituents or linkers present in compounds depicted in Table A.

In some embodiments, the compound is selected from any of the compoundsdepicted in Table A. In some embodiments, a compound comprises Formula(I), (II), and/or (III) and displays any suitable combination of thesubstituents depicted in the compounds of Table A.

In some embodiments, provided herein are pharmaceutical compositionscomprising a compound described herein (e.g., Formula (I), Formula (II),Formula (III), Table A, etc.) and a pharmaceutically acceptable carrier.In some embodiments, the pharmaceutical composition is formulated fororal administration, injection, or any suitable route of administration.

In some embodiments, provided herein are methods of inhibiting theactivity of PRC1 comprising contacting PRC1 or a component thereof withan effective amount of a compound described herein. In some embodiments,contacting comprises contacting a cell that expresses (e.g.,overexpresses, aberrantly expresses, etc.) PRC1 or a component thereof.

In some embodiments, provided herein are methods of treating a disease,comprising administering to a subject a pharmaceutical compositiondescribed herein in an amount effective to inhibit the activity of PRC1or a component thereof. In some embodiments, the disease is a cancer. Insome embodiments, the disease is a proliferative disorder. In someembodiments, the pharmaceutical composition is co-administered with anadditional cancer therapeutic. In some embodiments, the subject is ahuman.

In some embodiments, provided herein is the use of a compound describedherein. In some embodiments, provided herein is the use of a compounddescribed herein for inhibiting the activity of PRC1 or a componentthereof. In some embodiments, provided herein is the use of a compounddescribed herein for the treatment of a disease (e.g., cancer). In someembodiments, provided herein is the use of a compound described hereinfor the preparation of a medicament for the treatment of cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawings will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1. COMPOUND 1 binds to RING1B-BMI1. A. structure of COMPOUND 1. B.ITC experiments showing the binding of COMPOUND 1 to RING1B-BMI1. C.Assigned NMR spectrum of RING1B-BMI1 with DMSO and COMPOUND 1 in 1-2molar ratio.

FIG. 2. COMPOUND 1 inhibits PRC1 in vitro. A. COMPOUND 1 inhibitsRING1B-BMI1 H2Aub activity; B. COMPOUND 1 inhibits RING1B-PCGF1activity. C. COMPOUND 1 does not inhibit BRCA1-BARD1 and TRIM37 E3ligases. D. COMPOUND 1 inhibits RINIG1B-BMI1 interaction with nucleosomein EMSA assay.

FIG. 3. COMPOUND 1 inhibits PRC1 in K562 cells. Knockdown of BMI1 andRING1B in K562 cells results in decrease in H2Aub. Treatment withCOMPOUND 1 decreases H2Aub level in K562 cells.

FIGS. 4A-F. COMPOUND 1 inhibits PRC1 in TEX cells. FIG. 4A. Inhibitionof H2Aub in TEX cells. FIG. 4B. Differentiation of TEX cells upontreatment with COMPOUND 1. COMPOUND 103 is inactive analog that does notinduce differentiation. FIG. 4C. GSEA analysis of TEX cells showingrevers of stem cell signature. FIG. 4D. Morphology of TEX cells treatedwith COMPOUND 1 (active) and COMPOUND 103 (inactive) compounds. FIG. 4E.Gene expression changes upon treatment with COMPOUND 1. FIG. 4F.ChIP-seq analysis demonstrating global decrease in H2Aub in TEX cellsupon treatment with COMPOUND 1.

DEFINITIONS

Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsdescribed herein, some preferred methods, compositions, devices, andmaterials are described herein. However, before the present materialsand methods are described, it is to be understood that this invention isnot limited to the particular molecules, compositions, methodologies orprotocols herein described, as these may vary in accordance with routineexperimentation and optimization. It is also to be understood that theterminology used in the description is for the purpose of describing theparticular versions or embodiments only, and is not intended to limitthe scope of the embodiments described herein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. However, in case of conflict,the present specification, including definitions, will control.Accordingly, in the context of the embodiments described herein, thefollowing definitions apply.

As used herein and in the appended claims, the singular forms “a”, “an”and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “a PRC1 inhibitor is areference to one or more PRC1 inhibitors and equivalents thereof knownto those skilled in the art, and so forth.

As used herein, the term “and/or” includes any and all combinations oflisted items, including any of the listed items individually. Forexample, “A, B, and/or C” encompasses A, B, C, AB, AC, BC, and ABC, eachof which is to be considered separately described by the statement “A,B, and/or C.”

As used herein, the term “comprise” and linguistic variations thereofdenote the presence of recited feature(s), element(s), method step(s),etc. without the exclusion of the presence of additional feature(s),element(s), method step(s), etc. Conversely, the term “consisting of”and linguistic variations thereof, denotes the presence of recitedfeature(s), element(s), method step(s), etc. and excludes any unrecitedfeature(s), element(s), method step(s), etc., except forordinarily-associated impurities. The phrase “consisting essentially of”denotes the recited feature(s), element(s), method step(s), etc. and anyadditional feature(s), element(s), method step(s), etc. that do notmaterially affect the basic nature of the composition, system, ormethod. Many embodiments herein are described using open “comprising”language. Such embodiments encompass multiple closed “consisting of”and/or “consisting essentially of” embodiments, which may alternativelybe claimed or described using such language.

All chemical names of substituents should be interpreted in light ofIUPAC and/or a modified format in which functional groups within asubstituent are read in the order in which they branch from the scaffoldor main structure. For example, in the modified nomenclature,methyl-sulfonyl-propanol refers to CH₂SO₂CH₂CH₂CH₂OH or:

As another example, according to the modified nomenclature, amethyl-amine substituent is:

while an amino-methyl substituent is:

All chemical names of substituents should be interpreted in light ofIUPAC and/or the modified nomenclature and with reference to thechemical structures depicted and/or described herein.

As used herein, the term “subject” broadly refers to any animal,including but not limited to, human and non-human animals (e.g., dogs,cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). As usedherein, the term “patient” typically refers to a subject that is beingtreated for a disease or condition.

As used herein, the term “subject at risk for a disease,” for example,“a subject at risk for cancer” refers to a subject with one or more riskfactors for developing the disease (e.g., cancer). Depending upon thespecific disease, risk factors may include, but are not limited to,gender, age, genetic predisposition, environmental exposures,infections, and previous incidents of diseases, lifestyle, etc.

As used herein, the term “effective amount” refers to the amount of acomposition sufficient to effect beneficial or desired results. Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route.

As used herein, the terms “administration” and “administering” refer tothe act of giving a drug, prodrug, or other agent, or therapeutictreatment to a subject or in vivo, in vitro, or ex vivo cells, tissues,and organs. Exemplary routes of administration to the human body can bethrough space under the arachnoid membrane of the brain or spinal cord(intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical ortransdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear,rectal, vaginal, by injection (e.g., intravenously, subcutaneously,intratumorally, intraperitoneally, etc.) and the like.

As used herein, the terms “co-administration” and “co-administering”refer to the administration of at least two agent(s) (e.g., PRC1inhibitor and one or more additional therapeutics) or therapies to asubject. In some embodiments, the co-administration of two or moreagents or therapies is concurrent. In other embodiments, a firstagent/therapy is administered prior to a second agent/therapy. Those ofskill in the art understand that the formulations and/or routes ofadministration of the various agents or therapies used may vary. Theappropriate dosage for co-administration can be readily determined byone skilled in the art. In some embodiments, when agents or therapiesare co-administered, the respective agents or therapies are administeredat lower dosages than appropriate for their administration alone. Thus,co-administration is especially desirable in embodiments where theco-administration of the agents or therapies lowers the requisite dosageof a potentially harmful (e.g., toxic) agent(s), and/or whenco-administration of two or more agents results in sensitization of asubject to beneficial effects of one of the agents via co-administrationof the other agent.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invitro, in vivo or ex vivo.

The terms “pharmaceutically acceptable” or “pharmacologicallyacceptable,” as used herein, refer to compositions that do notsubstantially produce adverse reactions, e.g., toxic, allergic, orimmunological reactions, when administered to a subject.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers including, but not limitedto, phosphate buffered saline solution, water, emulsions (e.g., such asan oil/water or water/oil emulsions), and various types of wettingagents, any and all solvents, dispersion media, coatings, sodium laurylsulfate, isotonic and absorption delaying agents, disintigrants (e.g.,potato starch or sodium starch glycolate), and the like. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see, e.g., Martin,Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. (1975), incorporated herein by reference in its entirety.

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds herein are contemplated asbeing pharmaceutically acceptable. However, salts of acids and basesthat are non-pharmaceutically acceptable may also find use, for example,in the preparation or purification of a pharmaceutically acceptablecompound.

As used herein, the term “instructions for administering said compoundto a subject,” and grammatical equivalents thereof, includesinstructions for using the compositions contained in a kit for thetreatment of conditions (e.g., providing dosing, route ofadministration, decision trees for treating physicians for correlatingpatient-specific characteristics with therapeutic courses of action).

The term “carboxylic acid bioisostere” refers to a functional group ormoiety that exhibits similar physical, biological and/or chemicalproperties as a carboxylic acid moiety.

“Amino” refers to the —NH₂ moiety.

“Carbonyl” refers to a moiety of the formula —C(═O)—.

“Carboxy” or “carboxyl” refers to the —CO₂H moiety.

“Cyano” refers to the —CN moiety.

Hydroxy” or “hydroxyl” refers to the —OH moiety.

Imino” refers to the ═NH moiety. Unless stated otherwise specifically inthe specification, an imino group is optionally substituted.

“Nitro” refers to the —NO₂ moiety.

“Oxo” refers to the ═O moiety.

“Thioxo” refers to the ═S moiety.

“Acyl” refers to the group —C(═O)R_(a), where R_(a) is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon), heteroalkyl, and heterocyclylalkyl. Unless statedotherwise specifically in the specification, an acyl group is optionallysubstituted.

“Alkyl” refers to a straight or branched hydrocarbon chain moietyconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Alkyl includes alkenyls (one or more carbon-carbon double bonds)and alkynyls (one or more carbon-carbon triple bonds). Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted.

“Alkoxy” refers to a moiety of the formula —OR_(a) where R_(a) is analkyl group as defined herein containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, an alkoxygroup is optionally substituted.

“Alkylamino” refers to a moiety of the formula —NHR_(a), or —NR_(a)R_(b)where R_(a) and R_(b) are each independently an alkyl group as definedherein containing one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkylamino group is optionallysubstituted.

“Alkylaminoalkyl” refers to an alkyl moiety comprising at least onealkylamino substituent. The alkylamino substituent can be on a tertiary,secondary or primary carbon. Unless stated otherwise specifically in thespecification, an alkylaminoalkyl group is optionally substituted.

“Amide” or “amido” refers to a moiety with formula —C(═O)NR_(a)R_(b) or—NR_(a)C(═O) R_(b), where R_(a) and R_(b) are each independentlyselected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon), heteroalkyl, andheterocyclylalkyl, each of which moiety may itself be optionallysubstituted. In some embodiments, it is a C₁-C₄ amido or amide group,which includes the amide carbonyl in the total number of carbons in thegroup. The R_(a)R_(b) of —NR_(a)R_(b) of the amide may optionally betaken together with the nitrogen to which it is attached to form a 4-,5-, 6-, or 7-membered ring. Unless stated otherwise specifically in thespecification, an amido group is optionally substituted.

“Aminoalkyl” refers to an alkyl moiety comprising at least one aminosubstituent. The amino substituent can be on a tertiary, secondary orprimary carbon. Unless stated otherwise specifically in thespecification, an aminoalkyl group is optionally substituted.

“Aminocarbonyl” refers to an amide moiety of the formula—C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently H oralkyl. Unless stated otherwise specifically in the specification, anaminocarbonyl group is optionally substituted.

“Aryl” refers to a hydrocarbon ring system moiety comprising 6 to 18carbon atoms and at least one aromatic ring. For purposes of thisinvention, the aryl moiety is a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl moieties include, but are not limited to, aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl groups that are optionally substituted.

“Aralkyl” refers to a moiety of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined herein and R_(c) is one or more arylmoieties as defined herein, for example, benzyl, diphenylmethyl, and thelike. Unless stated otherwise specifically in the specification, anaralkyl group is optionally substituted.

“Aralkylamino” refers to a aralkyl-NR_(a)— moiety, where R_(a) is H oralkyl. Unless stated otherwise specifically in the specification, anaralkylamino is optionally substituted.

“Aralkyloxy” refers to an aralkyl-O— moiety. Unless stated otherwisespecifically in the specification, an aralkyloxy is optionallysubstituted.

“Arylamino” refers to a —NR_(a)-aryl moiety, where R_(a) is H or alkyl.Unless stated otherwise specifically in the specification, an arylaminois optionally substituted.

“Aryloxy” refers to an —O-aryl moiety. Unless stated otherwisespecifically in the specification, an aryloxy is optionally substituted.

“Bicycloalkyl” refers to a moiety with two cycloalkyl moieties, thathave two or more atoms in common. If the cycloalkyl moieties haveexactly two adjacent atoms in common they are said to be “fused”.Examples include, but are not limited to, bicyclo[3.1.0]hexyl,perhydronaphthyl, and the like. If the cycloalkyl moieties have morethan two atoms in common they are said to be “bridged”. Examplesinclude, but are not limited to, adamantyl, bicyclo[3.2.1]heptyl(“norbornyl”), bicyclo[2.2.2]octyl, and the like. Unless statedotherwise specifically in the specification, a bicycloalkyl isoptionally substituted.

“Carboxyalkyl” refers to a moiety of the formula —R_(b)—R_(c) whereR_(b) is an alkylene chain as defined herein and R_(c) is a carboxygroup as defined herein. Unless stated otherwise specifically in thespecification, carboxyalkyl group is optionally substituted.

“Cyanoalkyl” refers to a moiety of the formula —R_(b)—R_(c) where R_(b)is an alkylene chain as defined herein and R_(c) is a cyano group asdefined herein. Unless stated otherwise specifically in thespecification, a cyanoalkyl group is optionally substituted.

“Carbocycle” or “carbocyclic ring” refers to a saturated or unsaturated,non-aromatic, monocyclic or polycyclic hydrocarbon moiety, which mayinclude fused or bridged ring systems, having from three to fifteencarbon atoms, preferably having from three to ten carbon atoms,including cycloalkyls, cycloalkenyls, etc. “Cycloalkyl” refers to asaturated, non-aromatic, monocyclic or polycyclic hydrocarbon moiety,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms.Monocyclic cycloalkyl moieties include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl moieties include, forexample, adamantyl, norbornyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. A “cycloalkenyl” is acycloalkyl comprising one or more carbon-carbon double bonds within thering, such as cyclopentenyl and cyclohexenyl. Unless otherwise statedspecifically in the specification, a cycloalkyl group is optionallysubstituted.

“Cycloalkylalkyl” refers to a moiety of the formula —R_(b)R_(d) whereR_(b) is an alkylene chain as defined herein and R_(d) is a cycloalkylmoiety as defined herein. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group is optionally substituted.

“Cycloalkylalkylamino” refers to a cycloalkylalkyl-NR_(a)— moiety, whereR_(a) is H or alkyl and where the cycloalkylalkyl moiety is attached viaa carbon atom to nitrogen, wherein the nitrogen functions as a linker toattach the moiety to the remainder of the molecule. Unless statedotherwise specifically in the specification, a cycloalkylalkylamino isoptionally substituted.

“Cycloalkylalkyloxy” refers to a —O-cycloalkylalkyl moiety, where thecycloalkylalkyl moiety is attached via a carbon atom to oxygen, whereinthe oxygen functions as a linker to attach the moiety to the remainderof the molecule. Unless stated otherwise specifically in thespecification, a cycloalkylalkyloxy is optionally substituted.

“Cycloalkylamino” refers to a —NR_(a)-cycloalkyl moiety, where R_(a) isH or alkyl. Unless stated otherwise specifically in the specification, acycloalkylamino is optionally substituted.

“Cycloalkyloxy” refers to an —O-cycloalkyl moiety. Unless statedotherwise specifically in the specification, a cycloalkyloxy isoptionally substituted.

“Halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

“Haloalkyl” refers to an alkyl group, as defined herein, that issubstituted by one or more halo atoms, as defined herein, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, —CH₂CF₃,—CH₂CHF₂, —CH₂CH₂F, —CHFCF₃, —CHFCHF₂, —CHFCH₂F, —CHFCH₃, —CF₂CF₃,—CF₂CHF₂, —CF₂CH₂F, —CF₂CH₃, —CH₂CF₂CH₃, —CH₂CHFCH₃,3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless statedotherwise specifically in the specification, a haloalkyl group isoptionally substituted.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude any element other than carbon or hydrogen. Preferred heteroatomsare oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

“Heteroalkyl,” by itself or in combination with another term, means,unless otherwise stated, a straight or branched chain; monocyclic orpolycyclic moiety, which may include fused or bridged ring systems; orany combination thereof, comprising at least one carbon atom and atleast one heteroatom, such as O, N, P, Si and S, wherein one or moreheteroatoms may be oxidized. Heteroatom(s) may be positioned within thealkyl moiety, e.g., —CH₂—O—CH₂—; at a point of connectivity with theremainder of the molecule, e.g., —SO₂CH(CH₃)CH₂—; or a combinationthereof, e.g., —NH₂CH₂CH₂SO₂CH₂—. Unless stated otherwise specificallyin the specification, a heteroalkyl group is optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system moiety comprisingone to thirteen carbon atoms; one to six heteroatoms such as nitrogen,oxygen, and sulfur; and one or multiple rings wherein at least one ringis aromatic. For purposes of this invention, the heteroaryl group may bea monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which mayinclude fused or bridged ring systems and one or more heteroatoms may beoxidized. Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group is optionallysubstituted.

“Heteroarylalkyl” refers to a moiety of the formula —R_(b)R_(f) whereR_(b) is an alkylene chain as defined herein and R_(f) is a heteroarylgroup as defined herein. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group is optionally substituted.

“Heteroarylalkylamino” refers to a heteroarylalkyl-NR_(a)— moiety, whereR_(a) is H or alkyl. Unless stated otherwise specifically in thespecification, an heteroarylalkylamino is optionally substituted.

“Heteroarylalkyloxy” refers to an heteroarylalkyl-O— moiety. Unlessstated otherwise specifically in the specification, a heteroarylalkyloxyis optionally substituted.

“Heteroarylamino” refers to a —NR_(a)-heteroaryl moiety, where R_(a) isH or alkyl. Unless stated otherwise specifically in the specification, aheteroarylamino is optionally substituted.

“Heteroaryloxy” refers to an —O-heteroaryl moiety. Unless statedotherwise specifically in the specification, an heteroaryloxy isoptionally substituted.

“Heterobicycloalkyl” refers to a bicycloalkyl structure in which atleast one carbon ring atom is replaced with a heteroatom such as oxygen,nitrogen, and sulfur. Unless stated otherwise specifically in thespecification, a heterobicycloalkyl is optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a 3- to 18-memberednon-aromatic ring which consists of two to twelve carbon atoms and fromone to six heteroatoms such as nitrogen, oxygen, and sulfur. Unlessstated otherwise specifically in the specification, the heterocyclylgroup is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system,which may include fused or bridged ring systems; the heteroatoms may beoptionally oxidized; and the heterocyclyl may be unsaturated orsaturated. Examples of such heterocyclyl moieties include, but are notlimited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group is optionally substituted.

“Heterocyclylalkyl” or “heterocycloalkyl” refers to a moiety of theformula —R_(b)R_(e) where R_(b) is an alkylene chain as defined hereinand R_(e) is a heterocyclyl moiety as defined herein, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl isoptionally attached to the alkyl moiety at the nitrogen atom. Unlessstated otherwise specifically in the specification, a heterocyclylalkylgroup is optionally substituted.

“Heterocyclylalkylamino” refers to a heterocyclylalkyl-NR_(a)— moiety,where R_(a) is H or alkyl and where the heterocyclylalkyl moiety isattached via a carbon atom to nitrogen, wherein the nitrogen functionsas a linker to attach the moiety to the remainder of the molecule.Unless stated otherwise specifically in the specification, aheterocyclylalkylamino is optionally substituted.

“Heterocyclylalkyloxy” refers to a —O-heterocycloalkyl moiety, where theheterocyclylalkyl moiety is attached via a carbon atom to oxygen,wherein the oxygen functions as a linker to attach the moiety to theremainder of the molecule. Unless stated otherwise specifically in thespecification, a heterocyclylalkyloxy is optionally substituted.

“Heterocyclylamino” refers to a —NR_(a)-heterocyclyl moiety, where R_(a)is H or alkyl and where the heterocyclyl moiety is attached via a carbonatom to nitrogen, wherein the nitrogen functions as a linker to attachthe moiety to the remainder of the molecule. Unless stated otherwisespecifically in the specification, a heterocyclylamino is optionallysubstituted.

“Heterocyclyloxy” refers to an —O-heterocyclyl moiety, where theheterocyclyl moiety is attached via a carbon atom to oxygen, wherein theoxygen functions as a linker to attach the moiety to the remainder ofthe molecule. Unless stated otherwise specifically in the specification,a heterocyclyloxy is optionally substituted.

“Hydroxyalkyl” or “hydroxylalkyl” refers to an alkyl group comprising atleast one hydroxyl substituent. The —OH substituent may be on a primary,secondary, or tertiary carbon. Unless stated otherwise specifically inthe specification, a hydroxylalkyl group is optionally substituted.

“N-heteroaryl” refers to a heteroaryl moiety as defined hereincontaining at least one nitrogen and where the point of attachment ofthe heteroaryl moiety to the rest of the molecule is through a nitrogenatom in the heteroaryl ring. Unless stated otherwise specifically in thespecification, an N-heteroaryl group is optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl moiety as defined hereincontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl moiety to the rest of the molecule is through anitrogen atom in the heterocyclyl ring. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group is optionallysubstituted.

“Thioalkyl” refers to a moiety of the formula —SR_(a) where R_(a) is analkyl moiety as defined herein containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup is optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking two groups in a molecule, which may besaturated or unsaturated (i.e., contains one or more double and/ortriple bonds), and have from one to twelve carbon atoms, preferably oneto eight carbon atoms (C₁-C₈ alkylene) or one to six carbon atoms (C₁-C₆alkylene), e.g., methylene, ethylene, propylene, n-butylene, ethenylene,propenylene, n-butenylene, propynylene, n-butynylene, and the like. Thealkylene chain is attached to the rest of the molecule through a singleor double bond. The points of attachment of the alkylene chain to therest of the molecule may be through one carbon, e.g., methylene, or anytwo carbons within the chain, e.g., —CH₂CH(CH₃)CH₂CH₂—. Unless statedotherwise specifically in the specification, an alkylene chain isoptionally substituted.

“Alkylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—, whereR_(a) is an alkylene chain as defined herein. Unless stated otherwisespecifically in the specification, an alkylenecarbonyl is optionallysubstituted.

“Alkenylene” is an unsaturated alkylene, as defined herein, whichcomprises one or more carbon-carbon double bonds. Unless statedotherwise specifically in the specification, an alkenylene is optionallysubstituted.

“Alkenylenecarbonyl” refers to an unsaturated alkylenecarbonyl, asdefined herein, which comprises one or more carbon-carbon double bonds.Unless stated otherwise specifically in the specification, analkenylenecarbonyl is optionally substituted.

“Arylene” refers to a divalent aryl group which links one part of themolecule to another part of the molecule. Unless stated specificallyotherwise, an arylene is optionally substituted.

“Heteroalkylene” refers to an alkylene group comprising at least oneheteroatom (e.g., N, O or S). In some embodiments, the heteroatom iswithin the alkylene chain (i.e., the heteroalkylene comprises at leastone carbon-heteroatom-carbon bond). In other embodiments, the heteroatomis at a terminus of the alkylene and joins the alkylene to the remainderof the molecule (e.g., M1-H-A-M2, where M1 and M2 are portions of amolecule, H is a heteroatom and A is an alkylene). A heteroalkylene mayhave both internal and terminal heteroatoms, e.g., —OCH₂CH₂OCH₂CH₂O—.Unless stated otherwise specifically in the specification, aheteroalkylene is optionally substituted.

“Heteroalkylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—,where R_(a) is a heteroalkylene chain as defined herein. Unless statedotherwise specifically in the specification, a heteroalkylenecarbonyl isoptionally substituted.

“Heteroarylene” refers to a divalent heteroaryl group which links onepart of the molecule to another part of the molecule. Unless statedspecifically otherwise, a heteroarylene is optionally substituted.

“Heteroarylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—,wherein R_(a) is a heteroarylene as defined herein. Unless statedspecifically otherwise, a heteroarylenecarbonyl is optionallysubstituted.

“Heterocyclylalkylene” refers to a divalent heterocyclyl group whichlinks one part of the molecule to another part of the molecule. Unlessstated specifically otherwise, a heterocycloalkylene is optionallysubstituted.

“Heterocyclylalkylenecarbonyl” refers to a moiety of the formula—C(═O)R_(a)—, wherein R_(a) is a heterocycloalkylene as defined herein.Unless stated specifically otherwise, a heterocycloalkylenecarbonyl isoptionally substituted.

The term “substituted” used herein refers to replacement of at least onehydrogen atom with any of the above groups (e.g., amino, carboxy,hydroxyl, imino, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl,amide, aminoalkyl, aminocarbonyl, aryl, aralkyl, aralkylamino,aralkyloxy, arylamino, aryloxy, bicycloalkyl, carboxyalkyl, cyanoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkyloxy,cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom,heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylamino,heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterobicycloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino,heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl,N-heteroaryl, N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl,alkenylene, alkenylenecarbonyl, arylene, heteroalkylene,heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl,heterocyclylalkylene, and/or heterocyclylalkylenecarbonyl), wherein theat least one hydrogen atom is replaced by a bond to a non-hydrogen atomsuch as, but not limited to: a halogen atom such as F, Cl, Br, and I; anoxygen atom in groups such as hydroxyl groups, alkoxy groups, and estergroups; a sulfur atom in groups such as thiol groups, thioalkyl groups,sulfone groups such as alkyl sulfone groups, sulfonyl groups such assulfonamide groups and sulfonylalkyl groups such as sulfonylmethane, andsulfoxide groups such as alkyl sulfoxide groups; a nitrogen atom ingroups such as amino, amines, amides, alkylamines, dialkylamines,arylamines, alkylarylamines, diarylamines, N-oxides, imides, andenamines; a silicon atom in groups such as trialkylsilyl groups,dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilylgroups; a phosphorus atom in groups such as dialkylphosphine oxidegroups; and other heteroatoms in various other groups. “Substituted”also means any of the above groups in which one or more hydrogen atomsare replaced by a higher-order bond (e.g., a double- or triple-bond) toa carbon atom or a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. “Substituted” includes any of the above groupsin which one or more hydrogen atoms are replaced with —NR_(g)R_(h),—NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h),—NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g),—SO₂R_(g), —OSO₂R_(g), —SO₂O R_(g), ═NSO₂R_(g), —SO₂NR_(g)R_(h),—C(═O)R_(g), —C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), or—CH₂SO₂NR_(g)R_(h), where R_(g) and R_(h) are independently hydrogen,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.“Substituted” further means any of the above groups in which one or morehydrogen atoms are replaced by a bond to an amino, carbonyl, carboxy,cyano, hydroxyl, imino, nitro, oxo, thioxo, acyl, alkyl, alkoxy,alkylamino, alkylaminoalkyl, amide, aminoalkyl, aminocarbonyl, aryl,aralkyl, aralkylamino, aralkyloxy, arylamino, aryloxy, bicycloalkyl,carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkylamino, cycloalkylalkyloxy, cycloalkylamino,cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl,heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy,heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl,heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy,heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl,N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene,alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl,heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene,heterocyclylalkylenecarbonyl, trimethylsilanyl, dialkylphosphine oxide,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO(R^(a))₂, or—PO(OR^(a))₂ group, where each R^(a) is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl group. In addition,each of the foregoing substituents is optionally substituted with one ormore of the above substituents. The term “optionally substituted”, asused herein, means that the referenced group (e.g., alkyl, cycloalkyl,etc.) may or may not be substituted with one or more additionalgroup(s).

As used herein, the term “absent” when used in reference to functionalgroup or substituent, particularly in reference to the chemicalstructure of a compound, means that the particular functional group orsubstituent is not present in the compound being described. When used inreference to a substituent (e.g., a pendant group, not a linking group),the absence of the substituent typically means that the bond to thesubstituent is absent and that absence of the bond is compensated forwith a H atom. When used in reference to a position within a chain orring (e.g., a linking group, not a pendant group), the absence of theposition typically means that the two positions otherwise connected bythe absent position are either (1) directly connected by a covalentbond, or (2) not connected, as will either be apparent from thestructure or explicitly indicated.

As used herein, the terms “ring system” and “multiring system” refer toa chemical structure or moiety comprising two or more rings that shareat least one bond (and two or more atomic positions). For example, amultiring system comprising a cyclohexane and cyclopentane is:

If an aryl or heteroaryl ring is included in a multiring system, thearomaticity of the ring is maintained, unless described otherwise, forexample, a multiring system comprising a benzene and cyclohexane is:

DETAILED DESCRIPTION

Provided herein are small molecule inhibitors of Polycomb RepressiveComplex 1 (PRC1) activity, and methods of use thereof for the treatmentof disease, including leukemia and other cancers, as well as otherdiseases dependent on the activity of PRC1.

Aberrant expression of polycomb proteins has been frequently detected inhematological cancers (Refs. 4,5; herein incorporated by reference intheir entireties), and multiple studies emphasize that targetingpolycomb proteins has great therapeutic relevance to combathematological malignancies (Refs. 4, 6, 7; herein incorporated byreference in their entireties). Polycomb Repressive Complex 1 (PRC1) hasa well-established role in regulation of differentiation and maintenanceof stem cell populations (Ref. 8; herein incorporated by reference inits entirety). PRC1 has E3 ligase activity and catalyzes themonoubiquitylation of lysine 119 at histone H2A (H2AK119ub) by enzymaticaction of the two RING domain-containing proteins, Ring1B and Bmi1(Refs. 9,10; herein incorporated by reference in their entireties). Bmi1has been initially identified as an oncogene inducing B- and T-cellleukemias (ref. 11; herein incorporated by reference in its entirety).Bmi1 is a stem cell gene, which determines the proliferative andself-renewal capacity of normal and leukemic stem cells (Ref. 12; hereinincorporated by reference in its entirety). Silencing of Bmi1 profoundlyblocks cancer progression in multiple cancer models and numerous studiesidentified a strong correlation between high Bmi1 expression and poorsurvival in cancer patients (Refs. 13-19; herein incorporated byreference in their entireties). Bmi1 absolutely requires Ring1B to formactive Ring1B-Bmi1 E3 ligase critical for PRC1 activity (Refs. 10, 20,21; herein incorporated by reference in their entireties).

Experiments were conducted during development of embodiments herein todevelop small molecule inhibitors of PRC1 by targeting the Ring1B-BMI1E3 ligase. These compounds bind directly to Ring1B-Bmi1 withlow-micromolar affinity and inhibit PRC1 in vitro and in cells. Anexemplary compound (COMPOUND 1) binds directly to Ring1B-Bmi1 withKd=2.6 μM (FIG. 1) and inhibits E3 ligase activity with IC50˜2 uM (FIG.2). COMPOUND 1 is selective and does not inhibit other E3 ligases suchas BRCA1-BARD1 and TRIM37 (FIG. 2). COMPOUND 1 blocks the activity ofPRC1 complex in leukemia K562 cells (FIG. 3). Experiments were conductedduring development of embodiments herein to test COMPOUND 1 in leukemiastem cell models represented by TEX cells (Ref. 22; herein incorporatedby reference in its entirety) and M9-ENL1 cells (Ref. 23; hereinincorporated by reference in its entirety). COMPOUND 1 inhibits H2Aub inTEX cells and induces differentiation and loss of stem cell marker CD34(FIG. 4). RNA-seq and ChIP-seq experiments demonstrated reversingleukemia stem cell signature and global decrease in H2Aub (FIG. 4).COMPOUND 1 is also effective in blocking colony formation of M9-ENL1cells (FIG. 5). Treatment of M9-ENL1 cells with COMPOUND 1 followed bytransplantation into mice strongly decreases engraftment and leukemiadevelopment (FIG. 5). COMPOUND 1 also decreases H2Aub in primary AMLsamples, inhibits colony formation and decrease stem sell marker CD34(FIG. 6). In some embodiments, COMPOUND 1 and COMPOUND 1 analogs arefind use as agents in targeting leukemia and other cancer stem cells.

In some embodiments, PRC1 inhibitors herein comprise a substitutedpyrrole, furan, or thiophene ring. In some embodiments, PRC1 inhibitorsherein comprise Formula (I):

wherein R¹ is an aromatic ring, heteroaromatic ring, substitutedaromatic ring, or substituted heteroaromatic ring; wherein R² is analiphatic group (e.g., straight or branched aliphatic chain, substitutedor unsubstituted, etc.), cycloalkyl, or substituted cycloalkyl; whereinR³ is an aromatic ring, heteroaromatic ring, substituted aromatic ring,or substituted heteroaromatic ring; wherein R⁴ is a carboxylic acid(e.g., COOH, CH₂COOH, etc.), alcohol, tetrazole, ester, amide,sulfonamide, sulfone, phosphonate, heterocycle, etc., or a carboxylicacid bioisostere; wherein X is, NH, NR⁵, O, or S; and wherein R⁵, whenpresent, is straight or branched alkyl (e.g. CH₃), (CH₂)₁₋₆—COOH,(CH₂)₁₋₆—OH, NH₂, cycloalkyl, substituted cycloalkyl, amide. In someembodiments, R1, R2, R3, and R4 are any of the correspondingsubstituents depicted in the compounds of Table A.

In some embodiments, PRC1 inhibitors herein comprise a substitutedpyrrole, furan, or thiophene ring. In some embodiments, PRC1 inhibitorsherein comprise Formula (II):

wherein R² is an aliphatic group (e.g., straight or branched aliphaticchain (e.g. isopropyl, isobuthyl, etc.) substituted or unsubstituted),haloalkyl (e.g. mono-fluoro substituted straight or branched alkyl,di-fluoro substituted straight or branched alkyl, tri-fluoro substitutedstraight or branched alkyl, etc), cycloalkyl (e.g. cyclopropyl,cyclobuthyl, cyclopenthyl, etc.), or substituted cycloalkyl; wherein R⁴is a carboxylic acid (e.g., COOH, (CH₂)₁₋₅COOH, etc.), alcohol (e.g.—OH, (CH₂)₁₋₆OH, etc), tetrazole, ester, amide, —(CH₂)₁₋₅C(O)NH₂,sulfonamide, —(CH₂)₀₋₅SO₂NH₂, —(CH₂)₀₋₅SO₂CH₃, —NHSO₂NH₂, sulfone,phosphonate, heterocycle, etc., or a carboxylic acid bioisostere;wherein X is, NH, NR⁵, O, or S; wherein R⁵, when present, is straight orbranched alkyl (e.g. CH₃), (CH₂)₁₋₆—COOH, (CH₂)₁₋₆—CONH₂,(CH₂)₁₋₆—SO₂NH₂, (CH₂)₁₋₆—OH, NH₂, substituted alkyl, heteroalkyl,substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, amide;wherein A, A′, E, and E′ are independently selected from cycloalkyl,heteroalkyl, heterocycloalkyl, aryl, and heteroaryl rings (e.g., ringsof Table 1, phenyl ring, etc.) that are linked to form any suitablebicyclic ring systems (AA′ and EE′), such as the bicyclic ring systemsof Table 2, any suitable tricyclic rings made by combining a ring ofTable 1 (or phenyl ring) with a bicyclic ring of Table 2); whereinR^(A1-5), R^(A′1-5), R^(E1-5), and R^(E′1-5) may be absent or present,may be located at any position on the bicyclic ring system, may bepresent simultaneously at more than one position, and when present isselected from C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈branched alkyl (e.g. isopropyl, isobuthyl, etc.), substituted alkyl,haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc), C₁-C₈ alkoxy (e.g.methoxy, ethoxy, etc.), —OCF₃, —OH, —(CH₂)₁₋₆OH, ether (e.g.—(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.), —OR⁶, —(CH₂)₁₋₆OR⁶, amide (e.g.—(CH₂)₀₋₆CONH₂), substituted amide (e.g. —(CH₂)₀₋₅NHCOR⁶ (e.g. compounds176-180), —(CH₂)₀₋₅CONHR⁶ (e.g. compounds 198-200)) —NH₂, substitutedamine (—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶, carboxy (e.g.—(CH₂)₀₋₆COOH), sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substitutedsulfonamide (e.g. —(CH₂)₀₋₆SO₂NHR⁶), —(CH₂)₀₋₆SO₂CH₃, —(CH₂)₀₋₆SO₂CH₂R⁶,—NHSO₂NH₂, —NHSO₂NHR⁶, —NHSO₂CH₃, —NHSO₂CH₂R⁶, sulphone, phosphonate,—SH, —CN, halogen, heteroalkyl, substituted heteroalkyl, aryl,heteroaryl (e.g. tetrazole, triazole, isoxazole, thiadiazole, pyrazole,thiophene, etc.) or any suitable ring of Table 1; wherein R⁶, whenpresent, is C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈branched alkyl (e.g. isopropyl, isobuthyl, etc.), alkyne, alkene,substituted alkyl, haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc),C₁-C₈ alkoxy, —(CH₂)₁₋₆OH, ether (e.g. —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.),amide (e.g. —(CH₂)₁₋₆CONH₂), amine, substituted amine, heteroalkyl,C₃-C₈ saturated non-aromatic ring substituted or non-substituted, C₃-C₈heterocyclic saturated ring, aryl (e.g. phenyl), heteroaryl (e.g.tetrazole, triazole, isoxazole, thiadiazole, pyrazole, thiophene,pyridine, indole, etc.), or any suitable ring of Table 1, etc.

In some embodiments, PRC1 inhibitors herein comprise a substitutedpyrrole, furan, or thiophene ring. In some embodiments, PRC1 inhibitorsherein comprise Formula (II):

wherein R² is an aliphatic group (e.g., straight or branched aliphaticchain (e.g. isopropyl, isobuthyl, etc.) substituted or unsubstituted),haloalkyl (e.g. mono-fluoro substituted straight or branched alkyl,di-fluoro substituted straight or branched alkyl, tri-fluoro substitutedstraight or branched alkyl, etc), cycloalkyl (e.g. cyclopropyl,cyclobuthyl, cyclopenthyl, etc.), or substituted cycloalkyl; wherein R⁴is a carboxylic acid (e.g., COOH, (CH₂)₁₋₅COOH, etc.), alcohol (e.g.—OH, (CH₂)₁₋₆OH, etc), tetrazole, ester, amide, —(CH₂)₁₋₅C(O)NH₂,sulfonamide, —(CH₂)₀₋₅SO₂NH₂, —(CH₂)₀₋₅SO₂CH₃, —NHSO₂NH₂, sulfone,phosphonate, heterocycle, etc., or a carboxylic acid bioisostere;wherein X is, NH, NR⁵, O, or S; wherein R⁵, when present, is straight ofbranched alkyl (e.g. CH₃), (CH₂)₁₋₆—COOH, (CH₂)₁₋₆—CONH₂,(CH₂)₁₋₆—SO₂NH₂, (CH₂)₁₋₆—OH, NH₂, substituted alkyl, heteroalkyl,substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, amide;wherein R^(A1-3), R^(A′1-3), R^(E1-3), and R^(E′1-3) may be absent orpresent, may be located at any position on the bicyclic ring system, maybe present simultaneously at more than one position, and when present isselected from C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈branched alkyl (e.g. isopropyl, isobuthyl, etc.), substituted alkyl,haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc), C₁-C₈ alkoxy (e.g.methoxy, ethoxy, etc.), —OCF₃, —OH, —(CH₂)₁₋₆OH, ether (e.g.—(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.), —OR⁶, —(CH₂)₁₋₄R⁶, amide (e.g.—(CH₂)₀₋₆CONH₂), substituted amide (e.g. —(CH₂)₀₋₅NHCOR⁶ (e.g. compounds176-180), —(CH₂)₀₋₅CONHR⁶ (e.g. compounds 198-200)) —NH₂, substitutedamine (—NHR⁶), —(CH₂)₁₋₆NHR⁶, —(CH₂)₀₋₆SR⁶, carboxy (e.g.—(CH₂)₀₋₆COOH), sulfonamide (e.g. —(CH₂)₀₋₆SO₂NH₂), substitutedsulfonamide (e.g. —(CH₂)₀₋₆SO₂NHR⁶), —(CH₂)₀₋₆SO₂CH₃, —(CH₂)₀₋₆SO₂CH₂R⁶,—NHSO₂NH₂, —NHSO₂NHR⁶, —NHSO₂CH₃, NHSO₂CH₂R⁶; sulphone, phosphonate,—SH, —CN, halogen, heteroalkyl, substituted heteroalkyl, aryl,heteroaryl (e.g. tetrazole, triazole, isoxazole, thiadiazole, pyrazole,thiophene, etc.) or any suitable ring of Table 1; wherein R⁶, whenpresent, is C₁-C₈ alkyl (e.g. methyl, ethyl, propyl, etc.), C₁-C₈branched alkyl (e.g. isopropyl, isobuthyl, etc.), alkyne, alkene,substituted alkyl, haloalkyl (e.g. fluoro substituted alkyl, —CF₃, etc),C₁-C₈ alkoxy, —(CH₂)₁₋₆OH, ether (e.g. —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, etc.),amide (e.g. —(CH₂)₁₋₆CONH₂), amine, substituted amine, heteroalkyl,C₃-C₈ saturated non-aromatic ring substituted or non-substituted, C₃-C₈heterocyclic saturated ring, aryl (e.g. phenyl), heteroaryl (e.g.tetrazole, triazole, isoxazole, thiadiazole, pyrazole, thiophene,pyridine, indole, etc.), or any suitable ring of Table 1, etc.; whereinA¹⁻³ and E¹⁻³ are independently selected from CH₂, CH, NH, N, O and S(e.g., wherein two each of A¹⁻³ and/or E¹⁻³ are independently CH₂ or CHand one is NH, N, O, or S; wherein one each of A¹⁻³ and/or E¹⁻³ areindependently CH₂ or CH and two are NH, N, O, or S; etc.) wherein E⁴ isselected from CH or N; wherein the 5-member portions of the A and E ringsystems are independently selected from saturated 5-membered rings andaromatic 5-member rings (e.g., comprises one or more double bonds toresult in aromaticity of the ring).

In some embodiments, R¹ comprises an aromatic ring (or ring system(e.g., indole, phenyl, pyrdine, purine, etc.)). In some embodiments, R¹comprises an aromatic ring selected from the group consisting of furan,pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,benzene, pyridine, pyrazine, pyrimadine, pyridazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, benzofuran, isobenzofuran, indole,isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole,benzisoxazole, benzothiozole, napthalene, anthracene, quinoline,isoquinoline, quinoxaline, acridine, quinazoline, cinnoline,phthalazine, etc.

In some embodiments, the aromatic ring at R¹ is linked to the core ring(e.g., furan, pyrrole, or thiophene) of Formula (I) at any suitableposition on the aromatic ring. In some embodiments, the aromatic ring atR¹ is directly linked (e.g., by a single covalent bond) to the core ring(e.g., furan, pyrrole, or thiophene) of Formula (I). In someembodiments, the aromatic ring at R¹ is linked to the core ring (e.g.,furan, pyrrole, or thiophene) of Formula (I) by a linker moiety.Suitable linkers include 0-3 linearly connected C, S, O, and/or Nmembers, wherein any C or N members of the linker may be optionallysubstituted with any suitable substituent, such as CH₃, CH₂CH₃, CH═CH₂,OH, CH₂OH, OCH₃, NH₂, CH₂NH₂, NHCH₃, NO₂, SH, CH₂SH, SCH₃, Cl, Br, F, I,CH₂Cl, CH₂Br, CH₂F, CH₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃,CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, CH₂COOH, CONH₂,CH₂CONH₂, and combinations thereof. In some embodiments, R¹ comprises asubstituted aromatic ring. Any of the aforementioned R¹ aromatic ringsmay be substituted at one or more positions (e.g., 2, 3, 4, 5, 6, ormore, depending upon the size of the ring or ring system). In someembodiments, a substituent of an R¹ aromatic ring is selected from thegroup consisting of CH₃, (CH₂)₁₋₄CH₃, CH—CH₂, CH═CHCH₃, CH₂CH═CH₂, OH,(CH₂)₁₋₆OH, OCH₃, OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₄NH₂, NHCH₂CH₃, NHCH₃,NO₂, CH₂NHCH₃, SH, (CH₂)₁₋₆SH, SCH₃, CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl,(CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃,CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH,(CH₂)₁₋₆COOH, CONH₂, (CH₂)₁₋₆CONH₂, (CH₂)₁₋₆X(CH₃) where is X═O, NH, S,and combinations thereof. In some embodiments, an R¹ aromatic ringcomprises two or more substituents selected from the group consisting ofCH₃, (CH₂)₁₋₂CH₃, CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₄OH, OCH₃,OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₆NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, SH,(CH₂)₁₋₆SH, SCH₃, CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br,(CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CF₂H,CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, (CH₂)₁₋₆COOH, CONH₂,(CH₂)₁₋₆CONH₂, (CH₂)₁₋₆X(CH₃) where is X═O, NH, S, and combinationsthereof. In other embodiments, a substituent of an R¹ aromatic ringselected from the group consisting of alkyl₁₋₁₅, alkenyl₁₋₆, alkynyl₁₋₆,(CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH, (CH₂)₀₋₆C(O)NH(CH₂)₁₋₆,(CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl, sulfonamide, alkylsulfonamide,(CH₂)₀₋₆C(S)NH(CH₂)₁₋₆, (CH₂)₀₋₆O(CH₂)₁₋₆, (CH₂)₀₋₆OH,(CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH, (CH₂)₀₋₆NH(CH₂)₁₋₆,(CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆, (CH₂)₀₋₆NH₂, (CH₂)₀₋₆SO₂(CH₂)₁₋₆,(CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen (e.g., F, Cl, Br, or I),haloalkyl (e.g., (CH₂)₀₋₆ CH₂F, (CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar withBr, Cl, or I), dihaloalkyl (e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), trihaloalkyl (e.g.,(CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I), alkyl with 1-3 halogens attwo or more positions along its length, (CH₂)₁₋₆SP(Ph)₂═S,(CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₃C(O)O(CH₂)₀₋₃,(CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃, (CH₂)₀₋₃C(S)S(CH₂)₀₋₃,(CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, and (CH₂O)₁₋₆.

In some embodiments, R² is an aliphatic group (e.g., straight orbranched aliphatic chain, substituted or unsubstituted, etc.),cycloalkyl, or substituted cycloalkyl. In some embodiments, R² is analiphatic group comprising any suitable combination of 1-20 connectedcarbon atoms (e.g., connected by single, double, and/or triple bonds)and the requisite H (or D) atoms. In some embodiments, R² comprises analiphatic group selected from methane, acetylene, ethylene, ethane,propyne, propene, propane, isopropane, 1,2-butadiene, 1-butyne,1-butene, butane, isobutane, cyclopropane, cyclobutane, cyclopentane,cyclohexene, n-pentane, cycloheptane, methylcyclohexane, cubane, nonane,dicyclopentadiene, phellandrene, α-terpinene, limonene, undecane,squalene, polyethylene, etc.

In some embodiments, R² comprises a straight or branched aliphaticchain. In some embodiments, R² comprises a straight or branchedaliphatic chain comprising any suitable combination of 1-20 connectedcarbon atoms (e.g., connected by single, double, and/or triple bonds)and the requisite H (or D) atoms. Exemplary R² aliphatic chains includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, and longer (e.g., pentyl, hexyl, heptyl, octyl, nonyl,decyl, etc.) straight and/or branched (e.g., single branch, multiplebranches) aliphatic chains. In some embodiments, R² aliphatic chainscomprise with comprise one or more halogens (e.g., CL, Br, I, or F inplace of a H) or halogen containing groups (e.g., monohalogenated,dihalogenated, trihalogenated); suitable halogen containing groupsinclude: Cl, Br, F, I, CH₂Cl, CH₂Br, CH₂F, CH₂I, CHCl₂, CHBr₂, CHF₂,CHI₂, CCl₃, CBr₃, CF₃, and CI₃, which may comprise or be attached to anycarbon position of an R² aliphatic chain.

In some embodiments, R² comprises a cycloalkyl group. In someembodiments, R² comprises a cycloalkyl group selected fromcyclorpropane, cyclorpropene cyclobutane, cyclobutene, cyclopentane,cyclopentene, cycleohexane, cycleohexene, and larger cycloalkyl rings(e.g., pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), eithersaturated or comprising one or more double or triple bonds. In someembodiments, R₂ comprises an aliphatic ring system (e.g., two or morefused aliphatic rings (e.g., dicyclopentadiene)). In some embodiments, acycloalkyl or substituted cycloalkyl at R² is linked to the core ring(e.g., furan, pyrrole, or thiophene) at any suitable position on thearomatic ring. In some embodiments, the aliphatic ring at R² is directlylinked (e.g., by a single covalent bond) to the core ring (e.g., furan,pyrrole, or thiophene). In some embodiments, the aliphatic ring at R² islinked to the core ring (e.g., furan, pyrrole, or thiophene) by a linkermoiety. Suitable linkers include 0-3 linearly connected C, S, O, and/orN members, wherein any C or N members of the linker may be optionallysubstituted with any suitable substituent, such as CH₃, CH₂CH₃, CH═CH₂,OH, CH₂OH, OCH₃, NH₂, CH₂NH₂, NHCH₃, NO₂, SH, CH₂SH, SCH₃, Cl, Br, F, I,CH₂CI, CH₂Br, CH₂F, CH₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃,CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, CH₂COOH, CONH₂,CH₂CONH₂, and combinations thereof.

In some embodiments, R² comprises a substituted aliphatic ring. Any ofthe aforementioned R² aliphatic rings may be substituted at one or morepositions (e.g., 2, 3, 4, 5, 6, or more, depending upon the size of thering or ring system). In some embodiments, an substituent of an R²aliphatic ring selected from the group consisting of CH₃, (CH₂)₁₋₂CH₃,CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₂OH, OCH₃, OCH₂CH₃, CH₂OCH₃,NH₂, (CH₂)₁₋₂NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, SH, (CH₂)₁₋₂SH, SCH₃,CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I,CF₃, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, andcombinations thereof. In some embodiments, an R² aliphatic ringcomprises two or more substituents selected from the group consisting ofCH₃, (CH₂)₁₋₂CH₃, CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₂OH, OCH₃,OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₂NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, SH,(CH₂)₁₋₂SH, SCH₃, CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br,(CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CBr₃, CH₂CCl₃,CH₂CI₃, CN, and combinations thereof.

In some embodiments, R³ comprises an aromatic ring (or ring system(e.g., indole, phenyl, pyrdine, purine, etc.)). In some embodiments, R³comprises an aromatic ring selected from the group consisting of furan,pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,benzene, pyridine, pyrazine, pyrimadine, pyridazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, benzofuran, isobenzofuran, indole,isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole,benzisoxazole, benzothiozole, napthalene, anthracene, quinoline,isoquinoline, quinoxaline, acridine, quinazoline, cinnoline,phthalazine, etc.

In some embodiments, the aromatic ring at R³ is linked to the core ring(e.g., furan, pyrrole, or thiophene) of Formula (I) at any suitableposition on the aromatic ring. In some embodiments, the aromatic ring atR³ is directly linked (e.g., by a single covalent bond) to the core ring(e.g., furan, pyrrole, or thiophene) of Formula (I). In someembodiments, the aromatic ring at R³ is linked to the core ring (e.g.,furan, pyrrole, or thiophene) of Formula (I) by a linker moiety.Suitable linkers include 0-3 linearly connected C, S, O, and/or Nmembers, wherein any C or N members of the linker may be optionallysubstituted with any suitable substituent, such as CH₃, CH₂CH₃, CH═CH₂,OH, CH₂OH, OCH₃, NH₂, CH₂NH₂, NHCH₃, NO₂, SH, CH₂SH, SCH₃, Cl, Br, F, I,CH₂Cl, CH₂Br, CH₂F, CH₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃,CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, CH₂COOH, CONH₂,CH₂CONH₂, and combinations thereof. In some embodiments, R³ comprises asubstituted aromatic ring. Any of the aforementioned R³ aromatic ringsmay be substituted at one or more positions (e.g., 2, 3, 4, 5, 6, ormore, depending upon the size of the ring or ring system). In someembodiments, a substituent of an R³ aromatic ring is selected from thegroup consisting of CH₃, (CH₂)₁₋₆CH₃, CH═CH₂, CH═CHCH₃, CH₂CH═CH₂, OH,(CH₂)₁₋₄OH, OCH₃, OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₄NH₂, NHCH₂CH₃, NHCH₃,NO₂, CH₂NHCH₃, SH, (CH₂)₁₋₆SH, SCH₃, CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl,(CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃,CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH,(CH₂)₁₋₄COOH, CONH₂, (CH₂)₁₋₆CONH₂, (CH₂)₁₋₄X(CH₃) where is X═O, NH, S,and combinations thereof. In some embodiments, an R³ aromatic ringcomprises two or more substituents selected from the group consisting ofCH₃, (CH₂)₁₋₂CH₃, CH—CH₂, CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₄OH, OCH₃,OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₆NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, SH,(CH₂)₁₋₄SH, SCH₃, CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br,(CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CF₂H,CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH, (CH₂)₁₋₆COOH, CONH₂,(CH₂)₁₋₆CONH₂, (CH₂)₁₋₆X(CH₃) where is X═O, NH, S, and combinationsthereof. In other embodiments, a substituent of an R³ aromatic ringselected from the group consisting of alkyl₁₋₁₅, alkenyl₁₋₆, alkynyl₁₋₆,(CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH, (CH₂)₀₋₆C(O)NH(CH₂)₁₋₆.(CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl, sulfonamide, alkylsulfonamide,(CH₂)₀₋₆C(S)NH(CH₂)₁₋₆, (CH₂)₀₋₆(CH₂)₁₋₆, (CH₂)₀₋₆OH, (CH₂)₀₋₆S(CH₂)₁₋₆,(CH₂)₀₋₆SH, (CH₂)₀₋₆NH(CH₂)₁₋₆, (CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆, (CH₂)₀₋₆NH₂,(CH₂)₀₋₆SO₂(CH₂)₁₋₆, (CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen(e.g., F, Cl, Br, or I), haloalkyl (e.g., (CH₂)₀₋₆ CH₂F,(CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), dihaloalkyl(e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃ CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl,or I), trihaloalkyl (e.g., (CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I),alkyl with 1-3 halogens at two or more positions along its length,(CH₂)₁₋₄SP(Ph)₂═S, (CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₀₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆H(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₃C(O)O(CH₂)₀₋₃, (CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃,(CH₂)₀₋₃C(S)S(CH₂)₀₋₃, (CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, and (CH₂O)₁₋₆.

In some embodiments, R⁴ is a carboxylic acid (e.g., COOH, (CH₂)₁₋₅COOH),alcohol (e.g., —OH, (CH₂)₁₋₆OH), tetrazole, ester, amide,—(CH₂)₁₋₅C(O)NH₂, heterocycle (e.g. one of the heterocycles listedbelow), sulfone, sulfonamide, —(CH₂)₀₋₅SO₂NH₂, —(CH₂)₀₋₅SO₂CH₃,—NHSO₂NH₂, sulfone, phosphonate, or a carboxylic acid bioisostere. Insome embodiments, R⁴ is a carboxylic acid bioisostere, such as:

and the like.

In some embodiments, X is, NH, NR⁵, O, or S; and wherein R⁵, whenpresent, is, CH₂OH, —(CH₂)₁₋₆—COOH, CH₂SH, straight or branched alkyl(e.g. CH₃, CH₂CH₃), NH₂, CH₂NH₂, CH₂CN, (CH₂)₁₋₆—OH, NH₂, cycloalkyl,substituted cycloalkyl, amide.

In some embodiments, A, A′, E, and E′ are independently selected fromthe rings of Table 1. In some embodiments, AA′ and EE′ are independentlyselected from the rings of Table 2.

In some embodiments, each of R^(A1-5) (R^(A1), R^(A2), R^(A3), R^(A4),and R^(A5)), R^(A′1-5) (R^(A′1), R^(A′2), R^(A′3), R^(A′4), andR^(A′5)), R^(E1-5) (R^(E1), R^(E2), R^(E3), R^(E4), and R^(E5)), andR^(E′1-5) (R^(E′1), R^(E′2), R^(E′3), R^(E′4), and R^(E′5)) areindependently selected from any suitable substituent, such as CH₃,CH₂CH₃, CH═CH₂, OH, CH₂OH, OCH₃, NH₂, CH₂NH₂, NHCH₃, NO₂, SH, CH₂SH,SCH₃, Cl, Br, F, I, CH₂Cl, CH₂Br, CH₂F, CH₂I, CF₃, CF₂H, CFH₂, CBr₃,CCl₃, CI₃, CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃, CH₂CCl₃, CH₂CI₃, CN, COOH,CH₂COOH, CONH₂, CH₂CONH₂, and combinations thereof. In some embodiments,each of R^(A1-5) (R^(A1), R^(A2), R^(A3), R^(A4), and R^(A5)), R^(A′1-5)(R^(A′1), R^(A′2), R^(A′3), R^(A′4), and R^(A′5)), R^(E1-5) (R^(E1),R^(E2), R^(E3), R^(E4), and R^(E5)), and R^(E′1-5) (R^(E′1), R^(E′2),R^(E′3), R^(E′4), and R^(E′5)) are independently selected from isselected from the group consisting of CH₃, (CH₂)₁₋₆CH₃, CH═CH₂,CH═CHCH₃, CH₂CH═CH₂, OH, (CH₂)₁₋₆OH, OCH₃, OCH₂CH₃, CH₂OCH₃, NH₂,(CH₂)₁₋₄NH₂, NHCH₂CH₃, NHCH₃, NO₂, CH₂NHCH₃, SH, (CH₂)₁₋₆SH, SCH₃,CH₂SCH₃, Cl, Br, F, I, (CH₂)₁₋₂Cl, (CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I,CF₃. CF₂H, CFH₂, CBr₃, CCl₃, CI₃, CH₂CF₃, CH₂CF₂H, CH₂CFH₂, CH₂CBr₃,CH₂CCl₃, CH₂CI₃, CN, COOH, (CH₂)₁₋₆COOH, CONH₂, (CH₂)₁₋₆CONH₂,(CH₂)₁₋₆X(CH₃) where is X═O, NH, S, and combinations thereof. In someembodiments, each of R^(A1-5) (R^(A1), R^(A2), R^(A3), R^(A4), andR^(A5)), R^(A′1-5) (R^(A′1), R^(A′2), R^(A′3), R^(A′4), and R^(A′5)),R^(E1-5) (R^(E1), R^(E2), R^(E3), R^(E4), and R^(E5)), and R^(E′1-5)(R^(E′1), R^(E′2), R^(E′3), R^(E′4), and R^(E′5)) are independentlyselected from is selected from the group consisting of alkyl₁₋₁₅,alkenyl₁₋₆, alkynyl₁₋₆, (CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH,(CH₂)₀₋₆C(O)NH(CH₂)₁₋₆, (CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl,sulfonamide, alkylsulfonamide, (CH₂)₀₋₆C(S)NH(CH₂)₁₋₆,(CH₂)₀₋₆O(CH₂)₁₋₆, (CH₂)₀₋₆OH, (CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH,(CH₂)₀₋₆NH(CH₂)₁₋₆, (CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆, (CH₂)₀₋₆NH₂,(CH₂)₀₋₆SO₂(CH₂)₁₋₆, (CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen(e.g., F, Cl, Br, or I), haloalkyl (e.g., (CH₂)₀₋₆ CH₂F,(CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), dihaloalkyl(e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃ CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl,or I), trihaloalkyl (e.g., (CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I),alkyl with 1-3 halogens at two or more positions along its length,(CH₂)₁₋₄SP(Ph)₂═S, (CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₁₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅ NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₃C(O)O(CH₂)₀₋₃, (CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃,(CH₂)₀₋₃C(S)S(CH₂)₀₋₃, (CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, and (CH₂O)₁₄.

A compound of Formula (I), (II), and/or (III) may be selected fromcompounds listed in Table A (see EXPERIMENTAL section below). Compoundsof Formula (I), (II), and/or (III) that are not listed in Table A arealso within the scope herein. In some embodiments, compounds of Formula(I), (II), and/or (III) may comprise any of the substituents depicted inthe compounds of Table 2, in any suitable combinations. In someembodiments, compounds of Formula (I), (II), and/or (III) may comprisesubstituents not depicted in table A, but described elsewhere herein, inany suitable combination.

The compounds described herein may in some cases exist as diastereomers,enantiomers, or other stereoisomeric forms. The compounds presentedherein include all diastereomeric, enantiomeric, and epimeric forms aswell as the appropriate mixtures thereof. Separation of stereoisomersmay be performed by chromatography or by the forming diastereomeric andseparation by recrystallization, or chromatography, or any combinationthereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, hereinincorporated by reference for this disclosure). Stereoisomers may alsobe obtained by stereoselective synthesis.

In some embodiments, compounds may exist as tautomers. All tautomers areincluded within the formulas described herein.

Unless specified otherwise, divalent variables or groups describedherein may be attached in the orientation in which they are depicted orthey may be attached in the reverse orientation.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein may be in the form of pharmaceuticallyacceptable salts. As well, active metabolites of these compounds havingthe same type of activity are included in the scope of the presentdisclosure. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, etc. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

In some embodiments, compounds or salts described herein may beprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

To produce a prodrug, a pharmaceutically active compound is modifiedsuch that the active compound will be regenerated upon in vivoadministration. The prodrug can be designed to alter the metabolicstability or the transport characteristics of a drug, to mask sideeffects or toxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. In some embodiments, by virtueof knowledge of pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is determined, prodrugs of thecompound are designed. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985; Rooseboom et al., Pharmacological Reviews, 56:53-102,2004; Miller et al., J. Med Chem. Vol. 46, no. 24, 5097-5116, 2003;Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reportsin Medicinal Chemistry, Vol. 41, 395-407, 2006).

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by other means, including, but not limited to, the useof chromophores or fluorescent moieties, bioluminescent labels,photoactivatable or chemiluminescent labels, affinity labels (e.g.biotin), degradation tags (e.g. thalidomide conjugates (e.g., compounds198, 199, etc.), VHL ligand conjugates, etc.).

Compounds and salts described herein include isotopically-labeledcompounds. In general, isotopically-labeled compounds are identical tothose recited in the various formulae and structures presented herein,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber most common in nature. Examples of isotopes that can beincorporated into the present compounds include isotopes of hydrogen,carbon, nitrogen, oxygen, fluorine and chlorine, for example, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively. Certainisotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Further,substitution with isotopes such as deuterium, i.e., ²H, can affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

In some embodiments, compounds described herein, such as compounds ofFormula (I), (II), and/or (III) with any suitable substituents andfunctional groups disclosed herein, are in various forms, including butnot limited to, amorphous forms, milled forms and nano-particulateforms. In addition, compounds described herein include crystallineforms, also known as polymorphs. Polymorphs include the differentcrystal packing arrangements of the same elemental composition of acompound. Polymorphs usually have different X-ray diffraction patterns,melting points, density, hardness, crystal shape, optical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UV-VIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Pharmaceutical Compositions

In certain embodiments, compounds or salts of Formula (I), (II), and/or(III), with any suitable substituents and functional groups disclosedherein, are combined with one or more additional agents to formpharmaceutical compositions. Pharmaceutical compositions may beformulated in a conventional manner using one or more physiologicallyacceptable carriers including excipients and auxiliaries whichfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically. Proper formulation is dependent upon theroute of administration chosen. Additional details about suitableexcipients for pharmaceutical compositions described herein may befound, for example, in Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound or salt of Formula (I), (II), and/or (III), with any suitablesubstituents and functional groups disclosed herein, with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. In practicing the methods of treatment or use providedherein, therapeutically effective amounts of compounds described hereinare administered in a pharmaceutical composition to a mammal having adisease, disorder, or condition to be treated. In some embodiments, themammal is a human. A therapeutically effective amount can vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Thecompounds or salts of Formula (I), (II), and/or (III), with any suitablesubstituents and functional groups disclosed herein, can be used singlyor in combination with one or more therapeutic agents as components ofmixtures (as in combination therapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include a compound of Formula (I), (II), and/or (III), with anysuitable substituents and functional groups disclosed herein, can beformulated into any suitable dosage form, including but not limited to,aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries,suspensions, aerosols, fast melt formulations, effervescentformulations, lyophilized formulations, tablets, powders, pills,dragees, and capsules.

One may administer the compounds and/or compositions in a local ratherthan systemic manner, for example, via injection of the compounddirectly into an organ or tissue, often in a depot preparation orsustained release formulation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Furthermore, one mayadminister the drug in a targeted drug delivery system, for example, ina liposome coated with organ-specific antibody. The liposomes will betargeted to and taken up selectively by the organ. In addition, the drugmay be provided in the form of a rapid release formulation, in the formof an extended release formulation, or in the form of an intermediaterelease formulation.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compound ofFormula (I), (II), and/or (III), with any suitable substituents andfunctional groups disclosed herein, as an active ingredient in free-acidor free-base form, or in a pharmaceutically acceptable salt form.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipients with one or more of the compounds or salts ofFormula (I), (II), and/or (III), with any suitable substituents andfunctional groups disclosed herein, optionally grinding the resultingmixture, and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets, pills, or capsules. Suitableexcipients include, for example, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as,for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form,multiparticulate dosage forms, pellets, granules, or an aerosol. Inother embodiments, the pharmaceutical formulation is in the form of apowder. In still other embodiments, the pharmaceutical formulation is inthe form of a tablet, including but not limited to, a fast-melt tablet.Additionally, pharmaceutical formulations of the compounds describedherein may be administered as a single capsule or in multiple capsuledosage form. In some embodiments, the pharmaceutical formulation isadministered in two, or three, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound orsalt of Formula (I), (II), and/or (III), with any suitable substituentsand functional groups disclosed herein, with one or more pharmaceuticalexcipients to form a bulk blend composition. When referring to thesebulk blend compositions as homogeneous, it is meant that the particlesof the compound or salt of Formula (I), (II), and/or (III), with anysuitable substituents and functional groups disclosed herein, aredispersed evenly throughout the composition so that the composition maybe subdivided into equally effective unit dosage forms, such as tablets,pills, and capsules. The individual unit dosages may also include filmcoatings, which disintegrate upon oral ingestion or upon contact withdiluent. These formulations can be manufactured by conventionalpharmacological techniques.

The pharmaceutical solid dosage forms described herein can include acompound of Formula (I), (II), and/or (III), with any suitablesubstituents and functional groups disclosed herein, and one or morepharmaceutically acceptable additives such as a compatible carrier,binder, filling agent, suspending agent, flavoring agent, sweeteningagent, disintegrating agent, dispersing agent, surfactant, lubricant,colorant, diluent, solubilizer, moistening agent, plasticizer,stabilizer, penetration enhancer, wetting agent, anti-foaming agent,antioxidant, preservative, or one or more combination thereof. In stillother aspects, using standard coating procedures, such as thosedescribed in Remington's Pharmaceutical Sciences, 20th Edition (2000), afilm coating is provided around the formulation of the compounddescribed herein. In one embodiment, some or all of the particles of thecompound described herein are coated. In another embodiment, some or allof the particles of the compound described herein are microencapsulated.In still another embodiment, the particles of the compound describedherein are not microencapsulated and are uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound or salt of Formula (I), (II), and/or(III), with any suitable substituents and functional groups disclosedherein, from a solid dosage form matrix as efficiently as possible,disintegrants are often used in the formulation, especially when thedosage forms are compressed with binder. Disintegrants help rupturingthe dosage form matrix by swelling or capillary action when moisture isabsorbed into the dosage form.

Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, acellulose such as a wood product, methylcrystalline cellulose, e.g.,Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100,Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose,croscarmellose, or a cross-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. In some embodiments, formulators determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 5400 to about 7000, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

There is considerable overlap between additives used in the solid dosageforms described herein. Thus, the above-listed additives should be takenas merely exemplary, and not limiting, of the types of additives thatcan be included in solid dosage forms of the pharmaceutical compositionsdescribed herein.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating aids in patient compliance(e.g., Opadry® coatings or sugar coating). Film coatings includingOpadry® typically range from about 1% to about 3% of the tablet weight.In other embodiments, the compressed tablets include one or moreexcipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compound or salt of Formula(I), (II), and/or (III), with any suitable substituents and functionalgroups disclosed herein, and one or more excipients are dry blended andcompressed into a mass, such as a tablet, having a hardness sufficientto provide a pharmaceutical composition that substantially disintegrateswithin less than about 30 minutes, less than about 35 minutes, less thanabout 40 minutes, less than about 45 minutes, less than about 50minutes, less than about 55 minutes, or less than about 60 minutes,after oral administration, thereby releasing the formulation into thegastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds described herein, which sufficientlyisolate the compound from other non-compatible excipients.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When such salts are added to water, the acidsand the base react to liberate carbon dioxide gas, thereby causing“effervescence.” Examples of effervescent salts include, e.g., thefollowing ingredients: sodium bicarbonate or a mixture of sodiumbicarbonate and sodium carbonate, citric acid and/or tartaric acid. Anyacid-base combination that results in the liberation of carbon dioxidecan be used in place of the combination of sodium bicarbonate and citricand tartaric acids, as long as the ingredients were suitable forpharmaceutical use and result in a pH of about 6.0 or higher.

In other embodiments, the formulations described herein, which include acompound or salt of Formula (I), (II), and/or (III), with any suitablesubstituents and functional groups disclosed herein, are soliddispersions. Methods of producing such solid dispersions include, butare not limited to, for example, U.S. Pat. Nos. 4,343,789, 5,340,591,5,456,923, 5,700,485, 5,723,269, and U.S. patent publication no.2004/0013734. In still other embodiments, the formulations describedherein are solid solutions. Solid solutions incorporate a substancetogether with the active agent and other excipients such that heatingthe mixture results in dissolution of the drug and the resultingcomposition is then cooled to provide a solid blend which can be furtherformulated or directly added to a capsule or compressed into a tablet.Methods of producing such solid solutions include, but are not limitedto, for example, U.S. Pat. Nos. 4,151,273, 5,281,420, and 6,083,518.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of a compound or salt of Formula (I), (II), and/or(III), with any suitable substituents and functional groups disclosedherein, and at least one dispersing agent or suspending agent for oraladministration to a subject. The formulations may be a powder and/orgranules for suspension, and upon admixture with water, a substantiallyuniform suspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

The pharmaceutical compositions described herein may include sweeteningagents such as, but not limited to, acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tuttifruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol,or any combination of these flavoring ingredients, e.g., anise-menthol,cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream,vanilla-mint, and mixtures thereof.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms include, but are not limited to, forexample, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

There is overlap between the above-listed additives used in the aqueousdispersions or suspensions described herein, since a given additive isoften classified differently by different practitioners in the field, oris commonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in formulationsdescribed herein.

Potential excipients for intranasal formulations include, for example,U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Formulationssolutions in saline, employing benzyl alcohol or other suitablepreservatives, fluorocarbons, and/or other solubilizing or dispersingagents. See, for example, Ansel, H. C. et al., Pharmaceutical DosageForms and Drug Delivery Systems, Sixth Ed. (1995). Preferably thesecompositions and formulations are prepared with suitable nontoxicpharmaceutically acceptable ingredients. The choice of suitable carriersis highly dependent upon the exact nature of the nasal dosage formdesired, e.g., solutions, suspensions, ointments, or gels. Nasal dosageforms generally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents mayalso be present. Preferably, the nasal dosage form should be isotonicwith nasal secretions.

For administration by inhalation, the compounds described herein may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

Buccal formulations that include compounds described herein may beadministered using a variety of formulations which include, but are notlimited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and5,739,136. In addition, the buccal dosage forms described herein canfurther include a bioerodible (hydrolysable) polymeric carrier that alsoserves to adhere the dosage form to the buccal mucosa. The buccal dosageform is fabricated so as to erode gradually over a predetermined timeperiod, wherein the delivery of the compound is provided essentiallythroughout. Buccal drug delivery avoids the disadvantages encounteredwith oral drug administration, e.g., slow absorption, degradation of theactive agent by fluids present in the gastrointestinal tract and/orfirst-pass inactivation in the liver. With regard to the bioerodible(hydrolysable) polymeric carrier, virtually any such carrier can beused, so long as the desired drug release profile is not compromised,and the carrier is compatible with the compounds described herein, andany other components that may be present in the buccal dosage unit.Generally, the polymeric carrier comprises hydrophilic (water-solubleand water-swellable) polymers that adhere to the wet surface of thebuccal mucosa. Examples of polymeric carriers useful herein includeacrylic acid polymers and co, e.g., those known as “carbomers”(Carbopol®, which may be obtained from B.F. Goodrich, is one suchpolymer). Other components may also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions may take the form of tablets, lozenges, or gelsformulated in a conventional manner.

Transdermal formulations described herein may be administered using avariety of devices including but not limited to, U.S. Pat. Nos.3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097,3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894,4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299,4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983,6,929,801 and 6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound orsalt of Formula (I), (II), and/or (III), with any suitable substituentsand functional groups disclosed herein; (2) a penetration enhancer, and(3) an aqueous adjuvant. In addition, transdermal formulations caninclude additional components such as, but not limited to, gellingagents, creams and ointment bases, and the like. In some embodiments,the transdermal formulation can further include a woven or non-wovenbacking material to enhance absorption and prevent the removal of thetransdermal formulation from the skin. In other embodiments, thetransdermal formulations described herein can maintain a saturated orsupersaturated state to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds described herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Formulations suitable for intramuscular, subcutaneous, or intravenousinjection may include physiologically acceptable sterile aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, andsterile powders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and non-aqueous carriers,diluents, solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally recognized in the field. For other parenteral injections,appropriate formulations may include aqueous or nonaqueous solutions,preferably with physiologically compatible buffers or excipients. Suchexcipients are generally recognized in the field.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and are formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,medicated sticks, balms, creams or ointments. Such pharmaceuticalcompounds can contain solubilizers, stabilizers, tonicity enhancingagents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Generally, an agent, such as a compound of Formula (I), (II), and/or(III), with any suitable substituents and functional groups disclosedherein, is administered in an amount effective for amelioration of, orprevention of the development of symptoms of, the disease or disorder(i.e., a therapeutically effective amount). Thus, a therapeuticallyeffective amount can be an amount that is capable of at least partiallypreventing or reversing a disease or disorder. The dose required toobtain an effective amount may vary depending on the agent, formulation,disease or disorder, and individual to whom the agent is administered.

Determination of effective amounts may also involve in vitro assays inwhich varying doses of agent are administered to cells in culture andthe concentration of agent effective for ameliorating some or allsymptoms is determined in order to calculate the concentration requiredin vivo. Effective amounts may also be based in in vivo animal studies.

An agent can be administered prior to, concurrently with and subsequentto the appearance of symptoms of a disease or disorder. In someembodiments, an agent is administered to a subject with a family historyof the disease or disorder, or who has a phenotype that may indicate apredisposition to a disease or disorder, or who has a genotype whichpredisposes the subject to the disease or disorder.

In some embodiments, the compositions described herein are provided aspharmaceutical and/or therapeutic compositions. The pharmaceuticaland/or therapeutic compositions of the present invention can beadministered in a number of ways depending upon whether local orsystemic treatment is desired and upon the area to be treated.Administration can be topical (including ophthalmic and to mucousmembranes including vaginal and rectal delivery), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer, intratracheal, intranasal, epidermal and transdermal), oralor parenteral. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Compositions and formulations for topical administrationcan include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalcarriers; aqueous, powder, or oily bases; thickeners; and the like canbe necessary or desirable. Compositions and formulations for oraladministration include powders or granules, suspensions or solutions inwater or non-aqueous media, capsules, sachets or tablets. Thickeners,flavoring agents, diluents, emulsifiers, dispersing aids or binders canbe desirable. Compositions and formulations for parenteral, intrathecalor intraventricular administration can include sterile aqueous solutionsthat can also contain buffers, diluents and other suitable additivessuch as, but not limited to, penetration enhancers, carrier compoundsand other pharmaceutically acceptable carriers or excipients.Pharmaceutical and/or therapeutic compositions of the present inventioninclude, but are not limited to, solutions, emulsions, and liposomecontaining formulations. These compositions can be generated from avariety of components that include, but are not limited to, preformedliquids, self-emulsifying solids and self-emulsifying semisolids.

The pharmaceutical and/or therapeutic formulations, which canconveniently be presented in unit dosage form, can be prepared accordingto conventional techniques well known in thepharmaceutical/nutriceutical industries. Such techniques include thestep of bringing into association the active ingredients with thepharmaceutical carrier(s) or excipient(s). In general the formulationsare prepared by uniformly and intimately bringing into association theactive ingredients with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product. The compositionsof the present invention can be formulated into any of many possibledosage forms such as, but not limited to, tablets, capsules, liquidsyrups, soft gels, suppositories, and enemas. The compositions of thepresent invention can also be formulated as suspensions in aqueous,non-aqueous, oil-based, or mixed media. Suspensions can further containsubstances that increase the viscosity of the suspension including, forexample, sodium carboxymethylcellulose, sorbitol and/or dextran. Thesuspension can also contain stabilizers. In one embodiment of thepresent invention the pharmaceutical compositions can be formulated andused as foams. Pharmaceutical foams include formulations such as, butnot limited to, emulsions, microemulsions, creams, jellies andliposomes. While basically similar in nature these formulations vary inthe components and the consistency of the final product.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

Dosing and administration regimes are tailored by the clinician, orothers skilled in the pharmacological arts, based upon well-knownpharmacological and therapeutic considerations including, but notlimited to, the desired level of therapeutic effect, and the practicallevel of therapeutic effect obtainable. Generally, it is advisable tofollow well-known pharmacological principles for administratingchemotherapeutic agents (e.g., it is generally advisable to not changedosages by more than 50% at time and no more than every 3-4 agenthalf-lives). For compositions that have relatively little or nodose-related toxicity considerations, and where maximum efficacy isdesired, doses in excess of the average required dose are not uncommon.This approach to dosing is commonly referred to as the “maximal dose”strategy. In certain embodiments, the compounds are administered to asubject at a dose of about 0.01 mg/kg to about 200 mg/kg, morepreferably at about 0.1 mg/kg to about 100 mg/kg, even more preferablyat about 0.5 mg/kg to about 50 mg/kg. When the compounds describedherein are co-administered with another agent (e.g., as sensitizingagents), the effective amount may be less than when the agent is usedalone. Dosing may be once per day or multiple times per day for one ormore consecutive days.

Methods of Treatment

The present disclosure provides compounds and methods for inhibitingPRC1 activity. In certain embodiments, the disclosure provides compoundsthat bind to and/or inhibit PRC1 activity or a component thereof.

Inhibition of PRC1 activity may be assessed and demonstrated by a widevariety of ways known in the art. Non-limiting examples include measure(a) a direct decrease in PRC1 activity; (b) a decrease in cellproliferation and/or cell viability; (c) a change in the maintenanceand/or differentiation of stem cell (e.g., cancer stem cell)populations, (d) a decrease in the levels of downstream targets of PRC1activity; (e) decrease in tumor volume and/or tumor volume growth rate;and (f) decrease in cancer progression. Kits and commercially availableassays can be utilized for determining one or more of the above.

The disclosure provides compounds and methods for treating a subjectsuffering from a disease, comprising administering a compound or saltdescribed herein, for example, a compound or salt of Formula (I), (II),and/or (III), with any suitable substituents and functional groupsdisclosed herein, to the subject. In certain embodiments, the disease isselected from a disease associated with aberrant expression of polycombproteins and/or PRC1 activity (e.g., PRC1 L3 ligase activity). Incertain embodiments, the disease is mediated by PRC1 activity and/orexpression (e.g., aberrant expression, overexpression, etc.). In certainembodiments, the disease is leukemia, hematologic malignancies, solidtumor cancer, glioma, other cancers, etc.

In some embodiments, the disclosure provides a method for treatingcancer in a subject, comprising administering a compound or saltdescribed herein, for example, a compound or salt of Formula (I), (II),and/or (III), with any suitable substituents and functional groupsdisclosed herein, to the subject. In some embodiments, the cancer ismediated by a PRC1 expression (e.g., aberrant expression,overexpression, etc.) and/or activity (e.g., PRC1 L3 ligase activity).In certain embodiments, the cancer is leukemia, breast cancer, prostatecancer, pancreatic cancer, lung cancer, thyroid cancer, liver cancer,skin cancer, or a brain tumor.

In certain embodiments, the disclosure provides method of treating adisease in a subject, wherein the method comprises determining if thesubject has a PRC1-mediated condition (e.g., cancer) and administeringto the subject a therapeutically effective dose of a compound or saltdescribed herein, for example, a compound or salt of Formula (I), (II),and/or (III), with any suitable substituents and functional groupsdisclosed herein.

In some embodiments, PRC1 expression (e.g., aberrant expression,overexpression, etc.) and/or activity (e.g., PRC1 L3 ligase activity)has been identified in hematological malignancies, e.g., cancers thataffect blood, bone marrow and/or lymph nodes. Accordingly, certainembodiments are directed to administration of a compound or saltdescribed herein, for example, a compound or salt of Formula (I), (II),and/or (III), with any suitable substituents and functional groupsdisclosed herein, to a subject with a hematological malignancy. Suchmalignancies include, but are not limited to, leukemias and lymphomas.For example, the presently disclosed compounds can be used for treatmentof diseases such as ALL, AML, Chronic lymphocytic leukemia (CLL), smalllymphocytic lymphoma (SLL), Chronic myelogenous leukemia (CML), Acutemonocytic leukemia (AMoL), hairy cell leukemia, and/or other leukemias.In certain embodiments, the compounds or salts of the disclosure can beused for treatment of lymphomas such as all subtypes of Hodgkinslymphoma or non-Hodgkins lymphoma.

Determining whether a tumor, cancer, or subject expresses (e.g.,overexpresses, aberrantly expresses, etc.) PRC1 or components thereofmay be undertaken by assessing the nucleotide sequence encodingcomponents of PRC1 or by assessing the amino acid sequence of PRC1components. Methods for detecting nucleotide sequences encoding PRC1 orcomponents thereof are known by those of skill in the art. These methodsinclude, but are not limited to, polymerase chain reaction-restrictionfragment length polymorphism (PCR-RFLP) assays, polymerase chainreaction-single strand conformation polymorphism (PCR-SSCP) assays,real-time PCR assays, PCR sequencing, mutant allele-specific PCRamplification (MASA) assays, direct sequencing, primer extensionreactions, electrophoresis, oligonucleotide ligation assays,hybridization assays, TaqMan assays, SNP genotyping assays, highresolution melting assays and microarray analyses. Methods for detectingPRC1 or protein components thereof are known by those of skill in theart. These methods include, but are not limited to, detection using abinding agent, e.g., an antibody, specific for PRC1 or proteincomponents thereof, protein electrophoresis and Western blotting, anddirect peptide sequencing.

Methods for determining whether a tumor, cancer, or subject expresses(e.g., overexpresses, aberrantly expresses, etc.) PRC1 or proteincomponents thereof, or is mediated by PRC1 activity (e.g., E3 ligaseactivity) can use a variety of samples. In some embodiments, the sampleis taken from a subject having a tumor or cancer. In some embodiments,the sample is a fresh tumor/cancer sample. In some embodiments, thesample is a frozen tumor/cancer sample. In some embodiments, the sampleis a formalin-fixed paraffin-embedded sample. In some embodiments, thesample is processed to a cell lysate. In some embodiments, the sample isprocessed to DNA or RNA. In some embodiments, the sample is a bloodsample, a blood product (e.g., plasma, serum, etc.), or another bodilyfluid (e.g., urine, saliva, etc.).

In certain embodiments, the disclosure provides a method of inhibitingPRC1 activity (e.g., E3 ligase activity) in a sample, comprisingadministering the compound or salt described herein to said samplecomprising PRC1 or components thereof.

The disclosure provides methods for treating a disease by administeringa compound or salt of Formula (I), (II), and/or (III), with any suitablesubstituents and functional groups disclosed herein, to a subjectsuffering from the disease, wherein the compound binds PRC1 orcomponents thereof and/or inhibits PRC1 activity or activity ofcomponents thereof. In certain embodiments, the compound covalentlybinds to PRC1 or components thereof. In certain embodiments, thecompound noncovalently binds to PRC1 or components thereof.

The disclosure also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to the mammal atherapeutically effective amount of a compound or salt of Formula (I),(II), and/or (III), with any suitable substituents and functional groupsdisclosed herein. In some embodiments, the method relates to thetreatment of cancer such as acute myeloid leukemia, cancer inadolescents, adrenocortical carcinoma childhood, AIDS-related cancers,e.g., Lymphoma and Kaposi's Sarcoma, anal cancer, appendix cancer,astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer,bladder cancer, bone cancer, brain stem glioma, brain tumor, breastcancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypicalteratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervicalcancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyleoproliferative disorders, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductalcarcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrialcancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewingsarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eyecancer, fibrous histiocytoma of bone, gall bladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairycell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkinlymphoma, hypopharyngeal cancer, intraocular melanoma, islet celltumors, pancreatic neuroendocrine tumors, kidney cancer, laryngealcancer, lip and oral cavity cancer, liver cancer, lobular carcinoma insitu (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer withoccult primary, midline tract carcinoma, mouth cancer multiple endocrineneoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosisfungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferativeneoplasms, multiple myeloma, merkel cell carcinoma, malignantmesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma,nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC),oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovariancancer, pancreatic cancer, papillomatosis, paraganglioma, paranasalsinus and nasal cavity cancer, parathyroid cancer, penile cancer,pharyngeal cancer, pleuropulmonary blastoma, primary central nervoussystem (CNS) lymphoma, prostate cancer, rectal cancer, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer, stomach (gastric) cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicularcancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter, trophoblastictumor, unusual cancers of childhood, urethral cancer, uterine sarcoma,vaginal cancer, vulvar cancer, or Viral-Induced cancer. In someembodiments, the method relates to the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin,e.g., psoriasis, restenosis, or prostate, e.g., benign prostatichypertrophy (BPH). In some cases, the method relates to the treatment ofleukemia, hematologic malignancy, solid tumor cancer, prostate cancer,e.g., castration-resistant prostate cancer, breast cancer, Ewing'ssarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocyteleukemia, glioma, glioblastoma, liver cancer, e.g., hepatocellularcarcinoma, or diabetes.

Subjects that can be treated with compounds of the invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,stereoisomer, isotopologue, hydrate or derivative of the compounds,according to the methods of this invention include, for example,subjects that have been diagnosed as having acute myeloid leukemia,acute myeloid leukemia, cancer in adolescents, adrenocortical carcinomachildhood, AIDS-related cancers, e.g., Lymphoma and Kaposi's Sarcoma,anal cancer, appendix cancer, astrocytomas, atypical teratoid, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumors, Burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic/myeloproliferative neoplasms, multiplemyeloma, merkel cell carcinoma, malignant mesothelioma, malignantfibrous histiocytoma of bone and osteosarcoma, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, Viral-Induced cancer, leukemia, hematologic malignancy,solid tumor cancer, prostate cancer, castration-resistant prostatecancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma,hepatocellular carcinoma, liver cancer, or diabetes. In some embodimentssubjects that are treated with the compounds of the invention includesubjects that have been diagnosed as having a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin,e.g., psoriasis, restenosis, or prostate, e.g., benign prostatichypertrophy (BPH).

Some embodiments further provide methods of inhibiting PRC1 activity, bycontacting PRC1 or one or more components thereof with an effectiveamount of a compound or salt of Formula (I), (II), and/or (III), withany suitable substituents and functional groups disclosed herein (e.g.,by contacting a cell, tissue, or organ that expresses PRC1 or one ormore components thereof). In some embodiments, the methods are providedfor inhibiting PRC1 activity in a subject, including but not limited to,rodents and mammals, e.g., humans, by administering into the subject aneffective amount of a compound or salt of Formula (I), (II), and/or(III), with any suitable substituents and functional groups disclosedherein. In some embodiments, the percentage inhibition exceeds 25%, 30%,40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the disclosure provides methods of inhibiting PRC1activity in a cell by contacting the cell with an amount of a compoundof the invention sufficient to inhibit the activity. In someembodiments, the invention provides methods of inhibiting PRC1 activityin a tissue by contacting the tissue with an amount of a compound orsalt of Formula (I), (II), and/or (III), with any suitable substituentsand functional groups disclosed herein, sufficient to inhibit the PRC1activity in the tissue. In some embodiments, the invention providesmethods of inhibiting PRC1 activity in an organism (e.g., mammal, human,etc.) by contacting the organism with an amount of a compound or salt ofFormula (I), (II), and/or (III), with any suitable substituents andfunctional groups disclosed herein, sufficient to inhibit the PRC1activity in the organism.

The compositions containing the compounds or salts thereof describedherein can be administered for prophylactic and/or therapeutictreatments. In therapeutic applications, the compositions areadministered to a patient already suffering from a disease, in an amountsufficient to cure or at least partially arrest the symptoms of thedisease. Amounts effective for this use will depend on the severity andcourse of the disease, previous therapy, the patient's health status,weight, and response to the drugs, and the judgment of the treatingclinician. In prophylactic applications, compositions containing thecompounds or salts thereof described herein are administered to apatient susceptible to or otherwise at risk of a particular disease,disorder or condition (e.g., a subject that is in remission and/or haspreviously suffered from the particular disease, disorder or condition).Such an amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingclinician. When used prophylactically, administration of the drug(s)does not necessarily completely eliminate the risk of the disease, butinstead reduces the subject's risk of developing the disease (e.g., asevidenced by population studies and/or clinical trials).

In the case wherein the patient's condition does not improve, upon theclinician's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease.

In the case wherein the patient's status does improve, upon theclinician's discretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from about 10%to about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease andits severity, the identity (e.g., weight) of the subject or host in needof treatment, but can nevertheless be determined in a manner recognizedin the field according to the particular circumstances surrounding thecase, including, e.g., the specific agent being administered, the routeof administration, the condition being treated, and the subject or hostbeing treated. In general, however, doses employed for adult humantreatment will typically be in the range of about 0.02-about 5000 mg perday, in some embodiments, about 1-about 1500 mg per day. The desireddose may conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Therapies

Provided herein are methods for combination therapies in which an agentknown to modulate other pathways, or other components of the samepathway, or even overlapping sets of target enzymes are used incombination with a compound or salt of Formula (I), (II), and/or (III),with any suitable substituents and functional groups disclosed herein.In one aspect, such therapy includes but is not limited to thecombination of one or more compounds of the invention withchemotherapeutic agents, targeted agents, therapeutic antibodies, andradiation treatment, to provide a synergistic or additive therapeuticeffect.

In general, the compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and may, because ofdifferent physical and chemical characteristics, have to be administeredby different routes. The determination of the mode of administration andthe advisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of theclinician. The initial administration can be made according toestablished protocols recognized in the field, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the clinician.

In certain instances, it may be appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein, such as a compoundor salt of Formula (I), (II), and/or (III), with any suitablesubstituents and functional groups disclosed herein, is nausea, then itmay be appropriate to administer an anti-nausea agent in combinationwith the initial therapeutic agent. Or, by way of example only, thetherapeutic effectiveness of one of the compounds described herein maybe enhanced by administration of an adjuvant (i.e., by itself theadjuvant may have minimal therapeutic benefit, but in combination withanother therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, by way of example only, the benefitexperienced by a patient may be increased by administering one of thecompounds described herein with another therapeutic agent (which alsoincludes a therapeutic regimen) that also has therapeutic benefit. Inany case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

The particular choice of compounds used will depend upon the diagnosisand judgment of the condition of the patient and the appropriatetreatment protocol. The compounds may be administered concurrently(e.g., simultaneously, essentially simultaneously or within the sametreatment protocol) or sequentially, depending upon the nature of thedisease, disorder, or condition, the condition of the patient, and theactual choice of compounds used. The determination of the order ofadministration, and the number of repetitions of administration of eachtherapeutic agent during a treatment protocol, is well within theknowledge of the clinician after evaluation of the disease being treatedand the condition of the patient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature. Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease beingtreated and so forth. In addition, when co-administered with one or morebiologically active agents, the compound provided herein may beadministered either simultaneously with the biologically activeagent(s), or sequentially. If administered sequentially, the attendingphysician will decide on the appropriate sequence of administeringprotein in combination with the biologically active agent(s).

In any case, the multiple therapeutic agents (one of which is a compoundor salt of Formula (I), (II), and/or (III), with any suitablesubstituents and functional groups disclosed herein, may be administeredin any order or even simultaneously. If simultaneously, the multipletherapeutic agents may be provided in a single, unified form, or inmultiple forms (by way of example only, either as a single pill or astwo separate pills). One of the therapeutic agents may be given inmultiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, thedosage regimen actually employed can vary widely and therefore candeviate from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease, andthe timing of administering the composition containing a compound canvary. Thus, for example, the compounds can be used as a prophylactic andcan be administered continuously to subjects with a propensity todevelop conditions or diseases in order to prevent the occurrence of thedisease. The compounds and compositions can be administered to a subjectduring or as soon as possible after the onset of the symptoms. Theadministration of the compounds can be initiated within the first 48hours of the onset of the symptoms, preferably within the first 48 hoursof the onset of the symptoms, more preferably within the first 6 hoursof the onset of the symptoms, and most preferably within 3 hours of theonset of the symptoms. The initial administration can be via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over about 5 minutes to about 5 hours, a pill, acapsule, transdermal patch, buccal delivery, and the like, orcombination thereof. A compound is preferably administered as soon as ispracticable after the onset of a disease is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from 1 day to about 3 months. The length of treatmentcan vary for each subject, and the length can be determined using theknown criteria. For example, the compound or a formulation containingthe compound can be administered for at least 2 weeks, preferably about1 month to about 5 years.

Particularly when the compounds and pharmaceutical compositions hereinare used for treating cancer, they may be co-administered with one ormore chemotherapeutics. Many chemotherapeutics are presently known inthe art and can be used in combination with the compounds herein. Insome embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzyme inhibitors, topoisomerase inhibitors, protein-proteininteraction inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

Embodiments herein further relate to methods for using a compound orsalt of Formula (I), (II), and/or (III) with any suitable substituentsand functional groups disclosed herein, or pharmaceutical compositionsprovided herein, in combination with radiation therapy for inhibitingabnormal cell growth or treating the hyperproliferative disorder in themammal. Techniques for administering radiation therapy are known in theart, and these techniques can be used in the combination therapydescribed herein. The administration of the compound of the invention inthis combination therapy can be determined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

The compounds or pharmaceutical compositions herein are also used incombination with an amount of one or more substances selected fromanti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the invention and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (e.g., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-II, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the invention areAG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

In some embodiments, the compounds described herein are formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

In some embodiments, medicaments which are administered in conjunctionwith the compounds described herein include any suitable drugs usefullydelivered by inhalation for example, analgesics, e.g., codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen ornedocromil; anti-infectives, e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments are used inthe form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) or as solvates(e.g., hydrates) to optimize the activity and/or stability of themedicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Other suitable therapeutic agents for coadministration with compoundsherein also include agents for pain and inflammation such as histamineand histamine antagonists, bradykinin and bradykinin antagonists,5-hydroxytryptamine (serotonin), lipid substances that are generated bybiotransformation of the products of the selective hydrolysis ofmembrane phospholipids, eicosanoids, prostaglandins, thromboxanes,leukotrienes, aspirin, nonsteroidal anti-inflammatory agents,analgesic-antipyretic agents, agents that inhibit the synthesis ofprostaglandins and thromboxanes, selective inhibitors of the induciblecyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2,autacoids, paracrine hormones, somatostatin, gastrin, cytokines thatmediate interactions involved in humoral and cellular immune responses,lipid-derived autacoids, eicosanoids, β-adrenergic agonists,ipratropium, glucocorticoids, methylxanthines, sodium channel blockers,opioid receptor agonists, calcium channel blockers, membrane stabilizersand leukotriene inhibitors.

Additional therapeutic agents contemplated for co-administration withcompounds and compositions herein include diuretics, vasopressin, agentsaffecting the renal conservation of water, rennin, angiotensin, agentsuseful in the treatment of myocardial ischemia, anti-hypertensiveagents, angiotensin converting enzyme inhibitors, β-adrenergic receptorantagonists, agents for the treatment of hypercholesterolemia, andagents for the treatment of dyslipidemia.

Other therapeutic agents contemplated for co-administration withcompounds and compositions herein include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, Mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundherein include but are not limited to anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one may combine a compound of the presentinvention with sorafenib and/or avastin. For treating an endometrialdisorder, one may combine a compound of the present invention withdoxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). Fortreating ovarian cancer, one may combine a compound of the presentinvention with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one may combinea compound of the present invention with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one may combine a compound of the present invention with taxotere(taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/oravastin.

Further therapeutic agents that can be combined with a compound hereinare found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein may be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds herein will be co-administered with other agents as describedabove. When used in combination therapy, the compounds described hereinare administered with the second agent simultaneously or separately.This administration in combination can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration.That is, a compound described herein and any of the agents describedabove can be formulated together in the same dosage form andadministered simultaneously. Alternatively, a compound of the inventionand any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentinvention can be administered just followed by and any of the agentsdescribed above, or vice versa. In some embodiments of the separateadministration protocol, a compound of the invention and any of theagents described above are administered a few minutes apart, or a fewhours apart, or a few days apart.

In some embodiments, a compound described herein is co-administered withanother therapeutic agent effective in treating leukemia and/or othercancers. In some embodiments, a compound described herein isco-administered with one or more therapeutic agents approved for thetreatment of Acute Lymphoblastic Leukemia (ALL), for example: ABITREXATE(Methotrexate), ADRIAMYCIN PFS (Doxorubicin Hydrochloride), ADRIAMYCINRDF (Doxorubicin Hydrochloride), ARRANON (Nelarabine), AsparaginaseErwinia chrysanthemi, CERUBIDINE (Daunorubicin Hydrochloride), CLAFEN(Cyclophosphamide), CLOFARABINE, CLOFAREX (Clofarabine), CLOLAR(Clofarabine), Cyclophosphamide, Cytarabine, CYTOSAR-U (Cytarabine),CYTOXAN (Cyclophosphamide), Dasatinib, Daunorubicin Hydrochloride,Doxorubicin Hydrochloride, Erwinaze (Asparaginase Erwinia Chrysanthemi),FOLEX (Methotrexate), FOLEX PFS (Methotrexate), GLEEVEC (ImatinibMesylate), ICLUSIG (Ponatinib Hydrochloride), Imatinib Mesylate, MARQIBO(Vincristine Sulfate Liposome), Methotrexate, METHOTREXATE LPF(Methorexate), MEXATE (Methotrexate), MEXATE-AQ (Methotrexate),Nelarabine, NEOSAR (Cyclophosphamide), ONCASPAR (Pegaspargase),Pegaspargase, Ponatinib Hydrochloride, RUBIDOMYCIN (DaunorubicinHydrochloride), SPRYCEL (Dasatinib), TARABINE PFS (Cytarabine), VINCASARPFS (Vincristine Sulfate), Vincristine Sulfate, etc.

In some embodiments, a compound described herein is co-administered withone or more therapeutic agents approved for the treatment of AcuteMyeloid Leukemia (AML), for example: ADRIAMYCIN PFS (DoxorubicinHydrochloride), ADRIAMYCIN RDF (Doxorubicin Hydrochloride), ArsenicTrioxide, CERUBIDINE (Daunorubicin Hydrochloride), CLAFEN(Cyclophosphamide), Cyclophosphamide, Cytarabine, CYTOSAR-U(Cytarabine), CYTOXAN (Cyclophosphamide), Daunorubicin Hydrochloride,Doxorubicin Hydrochloride, NEOSAR (Cyclophosphamide), RUBIDOMYCIN(Daunorubicin Hydrochloride), RYDAPT (Midostaurin), TARABINE PFS(Cytarabine), TRISENOX (Arsenic Trioxide), VINCASAR PFS (VincristineSulfate), Vincristine Sulfate, etc.

In some embodiments, a compound described herein is co-administered withone or more therapeutic agents approved for the treatment of ChronicLymphocytic Leukemia (CLL), for example: Alemtuzumab, AMBOCHLORIN(Chlorambucil), AMBOCLORIN (Chlorambucil), ARZERRA (Ofatumumab),Bendamustine Hydrochloride, CAMPATH (Alemtuzumab), CHLORAMBUCILCLAFEN(Cyclophosphamide), Cyclophosphamide, CYTOXAN (Cyclophosphamide),FLUDARA (Fludarabine Phosphate), Fludarabine Phosphate, LEUKERAN(Chlorambucil), LINFOLIZIN (Chlorambucil), NEOSAR (Cyclophosphamide),Ofatumumab, TREANDA (Bendamustine Hydrochloride), etc.

In some embodiments, a compound described herein is co-administered withone or more therapeutic agents approved for the treatment of ChronicMyelogenous Leukemia (CML), for example: BOSULIF (Bosutinib), Bosutinib,CLAFEN (Cyclophosphamide), Cyclophosphamide, Cytarabine, CYTOSAR-U(Cytarabine), CYTOXAN (Cyclophosphamide), Dasatinib, GLEEVEC (ImatinibMesylate), ICLUSIG (Ponatinib Hydrochloride), Imatinib Mesylate, NEOSAR(Cyclophosphamide), Nilotinib, Omacetaxine Mepesuccinate, PonatinibHydrochloride, SPRYCEL (Dasatinib), SYNRIBO (Omacetaxine Mepesuccinate),TARABINE PFS (Cytarabine), TASIGNA (Nilotinib), etc.

In some embodiments, a compound described herein is co-administered withone or more therapeutic agents approved for the treatment of MeningealLeukemia, for example: CYTARABINE, CYTOSAR-U (Cytarabine), TARABINE PFS(Cytarabine), etc.

In some embodiments, a compound described herein is co-administered withone or more alkylating agents (e.g., for the treatment of cancer)selected from, for example, nitrogen mustard N-oxide, cyclophosphamide,ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine,apaziquone, brostallicin, bendamustine, carmustine, estramustine,fotemustine, glufosfamide, mafosfamide, bendamustin, mitolactol,cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin,and satraplatin.

In some embodiments, a compound described herein is co-administered withone or more anti-metabolites (e.g., for the treatment of cancer)selected from, for example, methotrexate, 6-mercaptopurineriboside,mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur,cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, fludarabin,5-azacitidine, capecitabine, cladribine, clofarabine, decitabine,eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea,melphalan, nelarabine, nolatrexed, ocfosf[iota]te, disodium premetrexed,pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate,vidarabine, vincristine, and vinorelbine;

In some embodiments, a compound described herein is co-administered withone or more hormonal therapy agents (e.g., for the treatment of cancer)selected from, for example, exemestane, Lupron, anastrozole,doxercalciferol, fadrozole, formestane, abiraterone acetate,finasteride, epristeride, tamoxifen citrate, fulvestrant, Trelstar,toremifene, raloxifene, lasofoxifene, letrozole, sagopilone,ixabepilone, epothilone B, vinblastine, vinflunine, docetaxel, andpaclitaxel;

In some embodiments, a compound described herein is co-administered withone or more cytotoxic topoisomerase inhibiting agents (e.g., for thetreatment of cancer) selected from, for example, aclarubicin,doxorubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin,9-aminocamptothecin, diflomotecan, irinotecan, topotecan, edotecarin,epimbicin, etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, etc.

In some embodiments, a compound described herein is co-administered withone or more anti-angiogenic compounds (e.g., for the treatment ofcancer) selected from, for example, acitretin, aflibercept, angiostatin,aplidine, asentar, axitinib, recentin, bevacizumab, brivanib alaninat,cilengtide, combretastatin, DAST, endostatin, fenretinide, halofuginone,pazopanib, ranibizumab, rebimastat, removab, revlimid, sorafenib,vatalanib, squalamine, sunitinib, telatinib, thalidomide, ukrain, andvitaxin.

In some embodiments, a compound described herein is co-administered withone or more antibodies (e.g., for the treatment of cancer) selectedfrom, for example, trastuzumab, cetuximab, bevacizumab, rituximab,ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept,oregovomab, and alemtuzumab.

In some embodiments, a compound described herein is co-administered withone or more VEGF inhibitors (e.g., for the treatment of cancer) selectedfrom, for example, sorafenib, DAST, bevacizumab, sunitinib, recentin,axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib,pazopanib, and ranibizumab.

In some embodiments, a compound described herein is co-administered withone or more EGFR inhibitors (e.g., for the treatment of cancer) selectedfrom, for example, cetuximab, panitumumab, vectibix, gefitinib,erlotinib, and Zactima.

In some embodiments, a compound described herein is co-administered withone or more HER2 inhibitors (e.g., for the treatment of cancer) selectedfrom, for example, lapatinib, tratuzumab, and pertuzumab; CDK inhibitoris selected from roscovitine and flavopiridol; In some embodiments, acompound described herein is co-administered with one or more proteasomeinhibitors (e.g., for the treatment of cancer) selected from, forexample, bortezomib and carfilzomib.

In some embodiments, a compound described herein is co-administered withone or more serine/threonine kinase inhibitors (e.g., for the treatmentof cancer), for example, MEK inhibitors and Raf inhibitors such assorafenib.

In some embodiments, a compound described herein is co-administered withone or more tyrosine kinase inhibitors (e.g., for the treatment ofcancer) selected from, for example, dasatinib, nilotibib, DAST,bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib,aflibercept, telatinib, imatinib mesylate, brivanib alaninate,pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, vectibix,gefitinib, erlotinib, lapatinib, tratuzumab, pertuzumab and midostaurin

In some embodiments, a compound described herein is co-administered withone or more androgen receptor antagonists (e.g., for the treatment ofcancer) selected from, for example, nandrolone decanoate,fluoxymesterone, Android, Prostaid, andromustine, bicalutamide,flutamide, apocyproterone, apoflutamide, chlormadinone acetate,Androcur, Tabi, cyproterone acetate, and nilutamide.

In some embodiments, a compound described herein is co-administered withone or more aromatase inhibitors (e.g., for the treatment of cancer)selected from, for example, anastrozole, letrozole, testolactone,exemestane, aminoglutethimide, and formestane.

In some embodiments, a compound described herein is co-administered withone or more other anti-cancer agents including, e.g., alitretinoin,ampligen, atrasentan bexarotene, borte-zomib, bosentan, calcitriol,exisulind, fotemustine, ibandronic acid, miltefosine, mitoxantrone,1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide,pegaspargase, pentostatin, tazaroten, velcade, gallium nitrate,canfosfamide, darinaparsin, and tretinoin. In a preferred embodiment,the compounds of the present disclosure may be used in combination withchemotherapy (e.g., cytotoxic agents), anti-hormones and/or targetedtherapies such as other kinase inhibitors, mTOR inhibitors andangiogenesis inhibitors.

In embodiments in which the compounds and pharmaceutical compositionsherein are used for the treatment or prevention of non-cancer diseasesand/or conditions, the compounds and pharmaceutical compositions hereinmay be co-administered with therapeutics and/or therapies known in thefield to be appropriate for the treatment of such diseases and/orconditions.

Kits

For use in the therapeutic and prophylactic applications describedherein, kits and articles of manufacture are also provided. In someembodiments, such kits comprise a carrier, package, or container that iscompartmentalized to receive one or more containers such as vials,tubes, and the like, each of the container(s) comprising one of theseparate elements to be used in a method described herein. Suitablecontainers include, for example, bottles, vials, syringes, and testtubes. The containers are formed from a variety of materials such asglass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes a compound or salt of Formula(I), (II), and/or (III) with any suitable substituents and functionalgroups disclosed herein, optionally in a composition or in combinationwith another agent as disclosed herein. The container(s) optionally havea sterile access port (for example the container is an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical composition is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack, for example, contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

EXPERIMENTAL

The compounds listed in Table A have been synthesized and/or tested foractivity in inhibiting activity of PRC1 complex, and are within thescope herein.

Example 1. Synthesis of3-(5-Chloro-1H-indol-4-yl)-5-(1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylicacid (1)

Methyl 6-chloro-2-methyl-3-nitrobenzoate (1-2)

To acid 1-1 (1 equiv., 2.5 g, 14.7 mol) in concentrated sulfuric acid(25 mL) at 0° C., nitric acid (68% aqueous, 15.9 M, 0.9 mL, 14.7 mmol)was added dropwise. After 10 minutes, the reaction was warmed to r.t.and stirred for another 2 hrs before poured into ice (100 mL). Themixture was extracted with ethyl acetate (3×50 mL). And the combinedorganic layer was washed with brine (100 mL), dried with magnesiumsulfate, filtered over celite, and concentrated on rotovap, to give 3.1g of crude product, which was used in the next step without furtherpurification. To a solution of nitro compound (1.0 equiv., 3.1 g, 14.4mmol) and dry DMF (catalytic amount, 100 μL) in dry toluene (30 mL) at0° C. under argon atmosphere, was added oxalylchloride (1.5 equiv., 2.7g, 1.8 mL), after 30 minutes, the reaction was warmed to r.t. and thenrefluxed for 3 hrs before removal of solvents on rotovap. After drying,the crude carboxylic chloride (1.0 equiv., 3.4 g, 14.4 mmol) wasdissolved anhydrous methanol (28.8 mL). The reaction was refluxed for 5hrs before removal of solvent. The resulting residue was purified withsilica gel flash chromatography to afford compound 1-2 (2.28 g, 68% over3 steps) as yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J=8.8 Hz,1H), 7.40 (d, J=8.8 Hz, 1H), 3.99 (s, 3H), 2.49 (s, 3H). ¹³C NMR (125MHz, CDCl₃) δ 166.03, 148.32, 136.64, 135.45, 132.08, 127.84, 126.09,77.00, 53.07, 17.00. HRMS [M+H]⁺ Calcd. for C₉H₉ClNO₄ 235.0215, found235.0212.

Methyl 5-chloro-1H-indole-4-carboxylate (1-3)

To a solution of 1-2 (1.0 equiv., 2.28 g, 9.9 mmol) in dry DMF (6 mL)under argon atmosphere, N,N-dimethylformamide di-iso-propylacetal (1.5equiv., 2.6 g, 3.1 mmol) was added. The reaction was heated ar 130° C.for 2 h before quenched with water (60 mL). After extraction with Et₂O(5×30 mL), the combined organic layer was washed with water (2×50 mL)and brine (60 mL), dried over magnesium sulfate, filtered over celite,and concentrated on rotovap, to give reddish crude product, which wasused in the next step without further purification. To a solution ofreddish intermediate in THF (HPLC grade, 24 mL), MeOH (HPLC grade, 24mL), and water (1 mL) at 0° C. under argon atmosphere, Raney Nickel(concentrated in water, 1 mL) was added, followed by dropwise additionof hydrazine hydrate (0.9 mL). The reaction was warmed to it and stirredfor 12 h, another portion of Raney Nickel (concentrated in water, 1 mL)and hydrazine hydrate (0.9 mL). After stirred another 12 hrs, themixture was filtered a short pad of silica gel and celite (washed withethyl acetate). The solvent was removed on rotovap, the residue wasdiluted with ethyl acetate (30 mL) and water (30 mL), After extractionwith ethyl acetate (5×30 mL), the combined organic layer was washed withbrine (60 mL), dried over magnesium sulfate, filtered over celite, andconcentrated on rotovap. The residue was purified with silica gel flashchromatography to afford the indole product 1-3 (1.87 g, 90% over 2steps) as yellow solid. ¹H NMR (500 MHz, cdcl₃) δ 8.51 (s, 1H),7.42-7.36 (m, 1H), 7.30 (dt, J=5.5, 2.8 Hz, 1H), 7.23 (dd, J=8.5, 4.9Hz, 1H), 6.74 (dd, J=2.0, 1.0 Hz, 1H), 4.04 (s, 3H). ¹³C NMR (125 MHz,cdcl₃) δ 167.12, 134.47, 128.00, 126.70, 125.17, 123.86, 122.06, 114.65,103.04, 77.00, 52.18. HRMS [M+H]⁺ Calcd. for C₁₀H₉ClNO₂ 210.0316, found210.0313.

Methyl 5-chloro-1-tosyl-1H-indole-4-carboxylate (1-4)

To a solution of 1-3 (1.0 equiv., 0.76 g, 5.2 mmol) in DCM (15 mL) at 0°C., potassium hydroxide (50%, aqueous, 7 mL) was added.Tetrabutylammonium hydrosulfate (0.1 equiv., 92.5 mg, 0.5 mmol) andtosylchloride (1.5 equiv., 1.5 g, 7.8 mmol) were added. The reactionmixture was stirred at room temperature for 3-5 hours. The mixture wasdiluted with ethyl acetate (50 mL), washed with water (2×20 mL), andbrine (30 mL). The organic layer was dried with anhydrous sodiumsulfate, filtered and concentrated. The residue was purified with silicagel column chromatography to give product (1.51 g, 91%) as pale yellowpowder. ¹H NMR (500 MHz, CDCl₃) δ 8.02 (d, J=8.9 Hz, 1H), 7.73 (d, J=8.3Hz, 2H), 7.65 (d, J=3.7 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.2Hz, 2H), 6.86 (d, J=3.7 Hz, 1H), 3.99 (s, 3H), 2.35 (s, 3H). ¹³C NMR(125 MHz, CDCl₃) δ 165.83, 145.53, 134.73, 133.29, 131.17, 130.04,128.55, 128.40, 126.75, 126.48, 123.35, 116.74, 108.57, 77.00, 52.39,21.54. HRMS [M+H]⁺ Calcd. for C₁₇H₁₅ClNO₄S 364.0405, found 364.0401.

5-Chloro-1-tosyl-1H-indole-4-carbaldehyde (1-5)

To a solution of ester 1-4 (1.0 equiv., 0.95 g, 2.6 mmol) in dry DCM (20mL) at 0° C. under argon atmosphere, DIBAL (2.14 equiv., 1.0 M in THF,0.8 mL, 0.8 mmol) was added dropwise. After stirred for 3 hrs, thereaction quenched with MeOH (1 mL) and aqueous Rochelle salt (20 mL).After extraction with DCM (3×15 mL), the combined organic layer waswashed with brine (50 mL), dried over magnesium sulfate, filtered overcelite, and concentrated on rotovap, to give crude alcohol, which wasused in the next step without further purification. To a solution ofintermediate alcohol in dry DCM (20 mL), NaHCO₃ (1.3 equiv., 287 mg, 3.4mmol) and Dess-Martin reagent (1.3 equiv., 1.447 g, 3.4 mmol) are addedrespectively. After stirred for 2 hrs, the reaction was quenched withaqueous sodium thiosulfate (20 mL). After extraction with DCM (3×15 mL),the combined organic layer was washed with brine (30 mL), dried overmagnesium sulfate, filtered over celite, and concentrated on rotovap.The residue was purified with silica gel flash chromatography to affordthe aldehyde product (810 mg, 92% over 2 steps) as yellow solid. ¹H NMR(500 MHz, CDCl₃) δ 10.65 (s, 1H), 10.65 (s, 1H), 8.16 (d, J=8.8 Hz, 1H),8.16 (d, J=8.8 Hz, 1H), 7.75 (dd, J=6.1, 2.2 Hz, 3H), 7.75 (dd, J=6.1,2.2 Hz, 3H), 7.57 (d, J=3.6 Hz, 1H), 7.57 (d, J=3.6 Hz, 1H), 7.37 (d,J=8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.30-7.22 (m, 3H), 7.26 (d, J=8.2Hz, 2H), 2.36 (s, 3H), 2.36 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 190.8,145.6, 135.0, 134.8, 133.9, 130.7, 130.5, 130.1, 126.8, 126.1, 124.3,119.8, 108.8, 21.6. HRMS [M+H]⁺ Calcd. for C₁₆H₁₃ClNO₃S 334.0299, found334.0297.

Ethyl3-(5-chloro-1-tosyl-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(1-6)

To a solution of 1-5 (1.0 eq) and 2-methyl-1-nitropropane (5.0 eq) indry THF (5 mL) was added DBU (0.1 eq) by syringe. The resultingyellow-orange solution was stirred at r.t. for 24 h. The mixture wasthen concentrated in vacuo to a yellow oil and directly subject to flashchromatography to get a beta-nitro alcohol as white solid. To a solutionof above-mentioned beta-nitro alcohol (1.0 eq) in anhydrous DCM wassubsequently added Ac₂O (2.0 eq), pyridine (2.0 eq), and DMAP (0.1 eq)at 0° C. The mixture was stirred at r.t. overnight. The reaction wasthen quenched with sat. aq. NH₄Cl, and extracted with DCM (3×10 mL). Thecombined organic layers were washed with aqueous 1 N hydrochloric acid,dried over sodium sulfate, filtrated and concentrated to get the acetatewithout further purification. To a mixture of acetate (1.0 eq), ethylisocyanoacetate (1.1 eq) in tert-butyl methyl ether (7.2 mL) at r.t. wasadded drop wise of DBU (2.1 eq). The reaction was stirred overnightbefore quenched with water (10 mL). The mixture was extracted with EtOAc(3×8 mL). The combined organic layers were washed with aqueous 1 Nhydrochloric acid (2×10 mL), brine, and dried over sodium sulfate. Afterfiltration and concentration, the residue was purified with silica gelcolumn chromatography (EtOAc/Hexane 4:1 to 3:1) to give desired pyrrolederivatives 1-6. Yield 10% for three steps. ¹H NMR (400 MHz, CDCl₃) δ9.20 (s, 1H), 7.90 (dd, J=8.8, 0.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.50(d, J=3.7 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 6.88(d, J=2.5 Hz, 1H), 6.25 (dd, J=3.6, 0.6 Hz, 1H), 3.91-3.79 (m, 2H),2.55-2.40 (m, 1H), 2.37 (s, 3H), 1.03 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.9Hz, 3H), 0.54 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 161.0,145.0, 135.1, 133.5, 132.7, 129.8, 129.2, 127.9, 126.9, 126.8, 125.2,123.4, 119.9, 118.2, 113.2, 109.0, 108.9, 59.6, 25.3, 23.7, 23.5, 21.6,13.3. HRMS [M+H]⁺ Calcd. for C₂₅H₂₆ClN₂O₄S 485.1296, found 485.1297.

Ethyl5-bromo-3-(5-chloro-1-tosyl-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(1-7)

To a mixture of 1-6 (1.0 eq) in THF (5 mL) was added N-bromosuccinimide(1.2 eq), then the mixture was stirred for 2 hrs at r.t. The mixture isfiltered and the solid is washed with cold DCM. The filtrate isevaporated and purified with column chromatography to give compound 1-7as a white solid. Yield 86%. ¹H NMR (500 MHz, CDCl₃) δ 9.74 (s, 1H),7.92 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.51 (d, J=3.4 Hz, 1H),7.37 (d, J=8.8 Hz, 1H), 7.25 (d, J=8.1 Hz, 2H), 6.26 (d, J=4.0 Hz, 1H),3.95-3.75 (m, 2H), 2.56 (hept, J=7.0 Hz, 1H), 2.37 (s, 3H), 1.05 (d,J=8.0 Hz, 3H), 1.01 (d, J=7.5 Hz, 3H), 0.47 (t, J=7.1 Hz, 3H). ¹³C NMR(125 MHz, CDCl₃) δ 160.2, 145.1, 135.1, 132.9, 132.7, 129.8, 129.7,129.5, 127.2, 127.1, 126.8, 125.2, 124.6, 120.5, 113.6, 108.8, 102.9,59.9, 26.2, 21.6, 21.5, 21.4, 13.2. HRMS [M+H]⁺ Calcd. forC₂₅H₂₅BrClN₂O₄S 563.0401, found 563.0400.

Ethyl3-(5-chloro-1-tosyl-1H-indol-4-yl)-5-(1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(1-8)

Ethyl 5-bromo-1H-pyrrole-2-carboxylate 1-7 (1.0 eq), 4-boronoindole (2.0eq), Pd(dppf)Cl₂ (0.05 eq) and Cs₂CO₃ (1.2 eq) were dissolved in mixtureof THF/H₂O (9/1, 10 mL). The resulting solution was degassed with argon.The mixture is then placed in a pre-heated oil bath at 80° C. for 12 hunder argon atmosphere, resulting in a black slurry. The mixture wascooled to room temperature, diluted with EtOAc (5 mL) and filteredthrough a Celite® plug eluting with additional ethyl acetate (2×3 mL).The resulting solution was washed with 1M of HCl (3×10 mL), saturatedaqueous NaHCO₃ solution (3×10 mL) and brine (10 mL). The organic layerwas dried over Na₂SO₄, filtered and evaporated in vacuo, the residue waspurified with column chromatograph to give compound 1-8 as white solid.Yield 89%. ¹H NMR (500 MHz, CDCl₃) δ 9.24 (s, 1H), 8.43 (s, 1H),7.96-7.88 (m, 1H), 7.76 (t, J=8.7 Hz, 2H), 7.56-7.50 (m, 1H), 7.48-7.37(m, 2H), 7.32-7.18 (m, 5H), 6.56 (s, 1H), 6.40 (s, 1H), 3.96-3.66 (m,2H), 3.00-2.80 (m, 1H), 2.35 (s, 3H), 0.91 (d, J=9.1, 3H), 0.79 (d,J=9.1, 3H), 0.48 (t, J=8.7 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 161.0,144.9, 135.9, 135.1, 133.2, 132.8, 132.4, 129.8, 129.3, 127.4, 126.9,126.8, 125.3, 124.82, 124.80, 124.78, 124.5, 121.8, 121.5, 119.1, 113.3,111.3, 109.7, 102.0, 59.4, 26.0, 23.4, 22.6, 21.5, 13.3. HRMS [M+H]⁺Calcd. for C₃₃H₃₁ClN₃O₄S 600.1718, found 600.1718.

3-(5-Chloro-1H-indol-4-yl)-5-(1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylicacid (1)

To a solution of compound 1-8 (1 eq) in methanol (5 mL) was added 1 MNaOH (5 mL, 10 eq). The mixture was refluxed for 4 h. The solvent isevaporated on a rotary evaporator to remove methanol and the solution isacidified with 1 M hydrochloric acid to give a white precipitate withsome slight foam. The solid is filtered and washed with water (2 mL).Finally, the solid was further purified with column chromatograph toobtain 1 as a white solid. Yield 69%. ¹H NMR (500 MHz, acetone) δ 10.48(s, 1H), 10.41 (s, 1H), 10.31 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.39 (d,J=9.6 Hz, 2H), 7.31 (s, 1H), 7.24-7.14 (m, 3H), 6.47 (d, J=0.9 Hz, 1H),6.23 (d, J=0.9 Hz, 1H), 2.82 (m, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.87 (d,J=7.1 Hz, 3H). ¹³C NMR (125 MHz, acetone) δ 162.5, 137.3, 135.3, 131.7,129.4, 129.3, 128.7, 127.1, 126.4, 126.3, 126.0, 125.9, 122.8, 122.1,121.8, 119.7, 112.2, 112.0, 103.3, 102.2, 27.0, 24.1, 23.0. HRMS [M+H]⁺Calcd. for C₂₄H₂₁ClN₃O₂ 418.1317, found 418.1313.

Example 2. Synthesis of4-(1,1-Difluoropropan-2-yl)-3,5-di(1H-indol-4-yl)-1H-pyrrole-2-carboxylicacid (30)

1-(tert-butyl) 2-Methyl 4-bromo-1H-pyrrole-1,2-dicarboxylate (30-2)

At r.t., boc anhydride (3.94 g, 18 mmol) was added to the solution of30-1 (3.07 g, 15 mmol) in MeCN (50 mL), followed by addition of DMAP(0.37 g, 3 mmol). After stirring for 2 h, the solvent was evaporated andthe residue was dissolved with ethyl acetate (50 mL), and washed withsat. aq. NH₄Cl (50 mL). The organic layer was dried over Na₂SO₄,evaporated in vacuo, and subject to flash chromatography to get thetitle compound as a colorless liquid (4.4 g, yield 95%). ¹H NMR (600MHz, Chloroform-d) δ 7.30 (d, J=1.9 Hz, 1H), 6.78 (d, J=1.9 Hz, 1H),3.84 (s, 3H), 1.57 (s, 9H).

1-(tert-Butyl) 2-methyl 4-(prop-1-en-2-yl)-1H-pyrrole-1,2-dicarboxylate(30-3)

To a solution of 30-2 (3.8 g, 12.5 mmol) in THF (60 mL) and water (12mL), potassium isopropenyl-trifluoroborate (3.7 mg, 25 mmol), Cs₂CO₃(12.2 g, 37.5 mmol), PPh₃ (328 mg, 1.25 mmol) and Pd(OAc)₂ (140 mg,0.625 mmol) was added. The mixture was heated to 80° C. overnight. Thesolvent was evaporated under pressure, then the residue was dissolvedwith ethyl acetate (50 mL) and washed with sat. aq. NaCl (50 mL). Theorganic phase was dried over Na₂SO₄, filtered, and evaporated in vacuoand subject to flash chromatography to obtain 30-3 as a colorless liquid(2.7 g, yield 81%). ¹H NMR (400 MHz, Chloroform-d) δ 7.26 (d, J=1.9 Hz,1H), 6.96 (d, J=1.9 Hz, 1H), 5.22 (s, 1H), 4.90 (t, J=1.5 Hz, 1H), 3.83(s, 3H), 2.02-1.96 (m, 3H), 1.56 (s, 11H).

1-(tert-Butyl) 2-methyl4-(1-hydroxypropan-2-yl)-1H-pyrrole-1,2-dicarboxylate (30-4)

To a cooled solution (0° C.) of 30-3 (1.9 g, 7.16 mmol) in of THF (40mL) under argon was added BH₃.DMS (2M THF solution 14.3 mL, 28.6 mmol).Then the reaction was allowed to warm to RT. The progress of thereaction was monitored by TLC. After 1 h, the analysis revealed completeconsumption of the starting material, H₂O₂(7.3 mL, 64 mmol) and 3.0 Msolution of NaOH (21.3 mL) in water were consecutively added at 0° C.After 20 min, the resulting mixture was extracted with ethyl acetate(3×25 mL). The combined organic phases were dried over Na2SO4, filteredand the filtrate was concentrated in vacuo. Purification by flashchromatography afforded 30-4 as a colorless liquid, diastereomericmixture (1.3 g, yield 64%). ¹H NMR (400 MHz, Chloroform-d) δ 7.15 (dd,J=1.9, 0.8 Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 3.81 (S, 3H), 3.66-3.51 (m,2H), 2.80 (h, J=6.8 Hz, 1H), 1.55 (s, 9H), 1.18 (d, J=7.0 Hz, 3H).

1-(tert-Butyl) 2-methyl4-(1-oxopropan-2-yl)-1H-pyrrole-1,2-dicarboxylate (30-5)

To a solution of 30-4 (416 mg, 1.47 mmol) in dry DCM (10 mL), NaHCO₃(160 mg, 1.9 mmol) and Dess-Martin-Periodinane (810 mg, 1.9 mmol) wereadded respectively. The solution was stirred at r.t. for 1 h, and thenquenched with sat. aq. NaSO₃ (10 mL), and the DCM was separated, theaqueous layer was extracted with DCM (2×10 mL), the combined organiclayer was washed with water, and dried over Na₂SO₄, filtered, andevaporated in vacuo. The residue was purified with flash columnchromatography to get a colorless liquid 30-5 (276 mg, yield 67%). ¹HNMR (600 MHz, Chloroform-d) δ 9.60 (s, 1H), 7.23-7.19 (m, 1H), 6.74 (d,J=1.9 Hz, 1H), 3.84 (s, 3H), 3.49 (q, J=7.0 Hz, 1H), 1.58 (s, 9H), 1.40(d, J=7.1 Hz, 3H).

1-(tert-Butyl) 2-methyl4-(1,1-difluoropropan-2-yl)-1H-pyrrole-1,2-dicarboxylate (30-6)

Compound 30-5 (276 mg, 0.98 mmol) was added to a solution of XtalFluor-E(343 mg, 1.5 mmol) and TEA.3HF (322 mg, 2 mmol) in DCM (10 mL) at −78°C. Then the mixture was allowed warm to r.t. and stirred overnight. Thereaction was quenched with 5% aq. sodium bicarbonate solution (5 mL) andstirred for 15 min, and the resulting mixture was extracted with DCM(2×5 ML). The organic phases were combined, dried over magnesiumsulfate, and filtered through a pad of silica gel. Solvents wereevaporated, and the resulting crude material was purified by silica gelflash chromatography to get 30-6 (200 mg, yield 67%) as a colorlessliquid. ¹H NMR (600 MHz, Chloroform-d) δ 7.21 (d, J=2.0 Hz, 1H), 6.78(d, J=2.0 Hz, 1H), 5.70 (td, J=56.7, 3.9 Hz, 1H), 3.84 (s, 3H),3.13-3.00 (m, 1H), 1.58 (s, 9H), 1.32 (d, J=7.2 Hz, 3H).

Methyl 3,5-dibromo-4-(1,1-difluoropropan-2-yl)-H-pyrrole-2-carboxylate(30-7)

TFA (1 mL) was added to a solution of 30-6 (200 mg, 0.66 mmol) in DCM(10 mL) at 0° C., then the mixture was warmed to r.t. and stirred for 1h. The solvent and excess TFA was evaporated in vacuo, then the residuewas dissolved in ethyl acetate and washed with sat aq. NaHCO₃. Theorganic layer was washed with water, and dried over Na₂SO₄, filtered,and evaporated. The residue was used for the next step directly withoutfurther purification.

The residue was dissolved in MeCN (5 mL), then NBS (367 mg, 1.32 mmol)was added at 0° C. The mixture was warmed to r.t. and stirred for 2.5hrs. Sat aq. sodium sulfite (5 mL) was added, the solution was extractedwith ethyl acetate (3×5 mL). The combined organic phase phase was driedover Na₂SO₄, filtered, and evaporated in vacuo and subject to flashchromatography to afford the 30-7 as a white solid (95 mg, 40% for twosteps). ¹H NMR (600 MHz, Chloroform-d) δ 9.17 (s, 1H), 6.09 (td, J=56.9,6.4 Hz, 1H), 3.90 (s, 3H), 3.44-3.32 (m, 1H), 1.45 (d, J=7.3 Hz, 3H).

4-(1,1-Difluoropropan-2-yl)-3,5-di(1H-indol-4-yl)-1H-pyrrole-2-carboxylicacid (30)

Compound 30-7 (95 mg, 0.26 mmol), indole-4-boronic (161 mg, 1.04 mmol),Cs₂CO₃ (362 mg, 1.04 mmol), and Pd(dppf)Cl₂ (20 mg, 0.026 mmol) wasdissolved in THF (10 mL) and water (1 mL). The mixture was heated to 80°C. overnight. The solvent was evaporated under pressure. The residue wasdissolved with ethyl acetate (10 mL) and washed with sat. aq. NaCl (10mL). The organic phase was dried over Na₂SO₄, filtered, and evaporatedin vacuo and subject to flash chromatography to get the ester precursoras a white solid (92 mg, yield 82%). MS(ESI⁺), [M+H]⁺ m/z 434.

A mixture of the ester precursor (92 mg, 0.21 mmol) and NaOH (5M, 0.42mL, 2.1 mmol) in THF/MeOH/H₂O (3/3/1 mL) was refluxed for 24 h. Thesolvent was evaporated, water and ethyl acetate were added to theresidue and acidify by 1M HCl. The organic phase was separated and driedover sodium sulfate. After filtration and concentration, the residuesubject to flash chromatography to afford compound 30 as a brown solid(75 mg, yield 85%). ¹H NMR (600 MHz, DMSO) δ 11.65 (s, 1H), 11.53 (s,1H), 11.25 (s, 1H), 11.06, 11.02 (s, 1H), 7.49 (d, J=8.10 Hz, 1H), 7.42(t, J=2.69 Hz, 1H), 7.37 (d, J=8.09 Hz, 1H), 7.30, 7.28 (t, J=2.72, 1H),7.20 (t, J=7.69 Hz, 1H), 7.15-7.10 (m, 1H), 7.09-7.05 (m, 1H), 6.95,6.88 (d, J=7.05 Hz, 1H), 6.33 (d, J=2.41 Hz, 1H), 6.12, 6.08 (t, J=2.31Hz, 1H), 5.49, 5.23 (td, J=7.55, 57.50 Hz, 1H), 3.08-2.85 (m, 1H), 0.90,0.74 (d, J=7.20 Hz, 3H). ¹³C NMR (150 Hz, DMSO) δ 161.7, 135.9, 135.87,135.84, 135.4, 133.58, 133.53, 128.8, 128.5, 128.4, 127.9, 127.7, 125,124.8, 124.6, 124.2, 124.0, 121.2, 121.0, 120.9, 120.7, 120.7, 120.4,120.3, 119.8, 119.6, 111.6, 110, 101.2, 100.6, 100.5, 36.0, 15.6, 15.3.HRMS calcd. for C₂₄H₁₉F₂N₃O₂[M+H]⁺ m/z 420.1518, found 420.1514.

Example 3. Synthesis of3-(2-chloro-3-methoxyphenyl)-5-(6-fluoro-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylicacid (57)

4-Bromo-6-fluoro-1H-indole (57-2)

To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (57-1) (10 g,42.7 mmol) in DMF (30 mL) at r.t. was slowly added DMF dimethylacetal(17 mL). The solution was heated at 110° C. for 12 h, then concentratedin vacuo to give a dark residue. To the residue in THF (100 mL) and MeOH(100 mL) at 0° C., Raney Nickel (10 mL) was added, followed by dropwiseaddition of hydrazine hydrate (10 mL). The reaction was warmed to r.t.and stirred for 12 h. The mixture was filtered a short pad of silica geland Celite. The solvents were evaporated, the residue was diluted withethyl acetate and water, the organic layer was separated and dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedwith silica gel flash chromatography to afford the indole product 57-2(5 g, yield 78%). ¹H NMR (600 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.56(dd, J=8.6, 5.4 Hz, 1H), 7.23-7.15 (m, 1H), 7.10 (d, J=11.0 Hz, 1H),6.97-6.86 (m, 1H), 6.57 (s, 1H).

6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole(57-3)

4-bromo-6-fluoro-1H-indole (57-2) (2.68 g, 12.5 mmol), p-toluenesulfonylchloride (3.17 g, 16.6 mmol) and tetrabutyl-ammonium hydrogen sulfate(500 mg, 1.25 mmol) was dissolved in DCM (60 mL). NaOH 5 M aq. (13 mL,65 mmol) was added and the mixture was stirred vigorously for 1 h.Diluted with water and DCM, collected the DCM phase and washed it twicewith water, dried and concentrated to give the residue as white solidwithout further purification.

To a solution of the residue in dioxane anhydrous under argon, was addedbis(pinacolato)diboron (3.81 g, 15 mmol), KOAc (3.68 g, 37.5 mmol), andPd(dppf)Cl₂ (306 mg, 0.375 mmol). The reaction mixture was stirred at80° C. for 12 h under argon. The mixture was cooled at r. L, filtrateover Celite and washed with ethyl acetate. To the reaction mixture wasadded water. The layers were separated and the aqueous phase wasextracted with ethyl acetate. The combined organic phases were washedwith brine, dried over anhydrous Na₂SO₄ and the solvent evaporated underreduced pressure. The residue obtained was purified by flashchromatography to get the title compound 57-3 as a white solid (5.2 g,yield 100% for two steps). ¹H NMR (600 MHz, Chloroform-d) δ 7.80 (dd,J=9.5, 2.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.56 (d, J=3.7 Hz, 1H), 7.43(dd, J=9.4, 2.4 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.13 (d, J=3.6 Hz, 1H),2.34 (s, 3H), 1.35 (s, 12H).

Methyl 4-isopropyl-1H-pyrrole-2-carboxylate (57-4)

Sodium methoxide (5.4M, 2.06 mL, 11.12 mmol) was added to a solution of1-(tert-butyl) 2-methyl 4-(prop-1-en-2-yl)-1H-pyrrole-1,2-dicarboxylate(30-3) (1.5 g, 5.56 mmol) in MeOH (15 mL), the mixture was stirred atr.t. for 20 mins. The reaction was quenched with water and extractedwith ethyl acetate (3×40 mL). The combined organic phase was dried overNa₂SO₄, filtered, and evaporated in vacuo and the residue was used fornext step directly without further purification.

To the solution of the residue in MeOH (30 mL) at r.t. Pd/C (90 mg) wasadded, and then the mixture was stirred overnight. The mixture wasfiltered and the solvent was evaporated, the resulting residue wassubject to flash column chromatography to get a white solid 57-4 (1.3 g,yield 95%). ¹H NMR (600 MHz, Chloroform-d) δ 8.99 (s, 1H), 6.80 (s, 1H),6.75 (s, 1H), 3.83 (s, 3H), 2.87-2.78 (m, 1H), 1.21 (d, J=6.9 Hz, 6H).

Methyl 5-bromo-4-isopropyl-1H-pyrrole-2-carboxylate (57-5)

NBS (454 mg, 2.54 mmol) was added to the compound 57-4 (424 mg, 2.54mmol) in THF (10 mL) solution at 0° C., the mixture was stirred for 2 h,and then quenched with sat. aq. sodium sulfite (5 mL) was added, thesolution was extracted with ethyl acetate (3×5 mL). The combined organicphase was dried over Na₂SO₄, filtered, and evaporated in vacuo andsubject to flash chromatography to afford the desired product 57-5 as awhite solid (560 mg, yield 90%). ¹H NMR (600 MHz, Chloroform-d) δ 9.93(s, 1H), 6.77 (d, J=3.0 Hz, 1H), 3.88 (s, 3H), 2.88-2.77 (m, 1H), 1.19(d, J=7.6 Hz, 6H).

Methyl5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(57-6)

Compound 57-5 (1.5 g, 6.1 mmol), 57-3 (2.53 g, 6.1 mmol), Cs₂CO₃ (3.97g, 12.2 mmol), and Pd(dppf)Cl₂ (249 mg, 0.3 mmol) was dissolved in THF(30 mL) and water (3 mL). The mixture was heated to 80° C. overnight.The solvent was evaporated under pressure. The residue was dissolvedwith ethyl acetate (60 mL) and washed with sat. aq. NaCl. The organicphase was dried over Na₂SO₄, filtered, and evaporated in vacuo andsubject to flash chromatography to afford the desired compound 57-6(2.36 g, yield 85%). ¹H NMR (600 MHz, Chloroform-d) δ 9.02 (s, 1H), 7.80(d, J=8.4 Hz, 2H), 7.73 (dd, J=9.3, 2.3 Hz, 1H), 7.58 (d, J=3.7 Hz, 1H),7.29 (d, J=8.1 Hz, 2H), 7.01 (dd, J=9.8, 2.2 Hz, 1H), 6.93 (d, J=2.6 Hz,1H), 6.61 (d, J=3.7 Hz, 1H), 3.79 (s, 3H), 2.93-2.85 (m, 1H), 2.38 (s,3H), 1.15 (d, J=6.9 Hz, 6H).

Methyl3-bromo-5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(57-7)

NBS (0.92 g, 5.2 mmol) was added to the solution of 57-6 (2.36 g, 5.2mmol) in THF (20 mL) at r.t., the mixture was stirred for 3.5 h, andthen quenched with sat. aq. sodium sulfite (15 mL) was added, thesolution was extracted with ethyl acetate (3×25 mL). The combinedorganic phase was dried over Na₂SO₄, filtered, and evaporated in vacuoand subject to flash chromatography to afford the desired product 57-7as a white solid (2.6 g, yield 92%). ¹H NMR (600 MHz, Chloroform-d) δ8.95 (s, 1H), 7.83-7.76 (m, 3H), 7.59 (d, J=3.7 Hz, 1H), 7.29 (d, J=8.1Hz, 2H), 6.96 (dd, J=9.4, 2.2 Hz, 1H), 6.51 (d, J=3.7 Hz, 1H), 3.86 (d,J=1.3 Hz, 3H), 3.04-2.94 (m, 1H), 2.39 (s, 3H), 1.23 (d, J=7.2 Hz, 6H).

3-(2-Chloro-3-methoxyphenyl)-5-(6-fluoro-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylicacid (57)

Compound 57-7 (213 mg, 0.4 mmol), (2-chloro-3-methoxyphenyl)boronic acid(57-8) (210 mg, 1.2 mmol), K₃PO₄ (242 mg, 1.2 mmol), Pd(OAc)₂ (4.2 mg,0.02 mmol), and DPE-Phos (20 mg, 0.04 mmol) was dissolved in toluene (10mL). The mixture was heated to 110° C. overnight. The solvent wasevaporated under pressure. The residue was dissolved with ethyl acetate(10 mL) and washed with sat. aq. NaCl (10 mL). The organic phase wasdried over Na₂SO₄, filtered, and evaporated in vacuo and subject toflash chromatography to get the ester precursor as a white solid (44 mg,yield 20%). MS(ESI⁺), [M+H]⁺ m/z 596.

A mixture of the ester precursor (44 mg, 0.074 mmol) and NaOH (5M, 0.15mL, 0.74 mmol) in THF/MeOH/H₂O (3/3/1 mL) was refluxed for 24 h. Thesolvent was evaporated, water and ethyl acetate were added to theresidue and acidify by 1M HCl. The organic phase was separated and driedover sodium sulfate. After filtration and concentration, the residuesubject to flash chromatography to afford compound 57 as a white solid(20 mg, yield 64%). ¹H NMR (600 MHz, Acetone-d₆) δ 10.60 (s, 1H), 10.55(s, 1H), 7.40 (t, J=2.8 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.25 (dd,J=9.8, 2.3 Hz, 1H), 7.08 (dd, J=8.3, 1.4 Hz, 1H), 7.05 (dd, J=7.6, 1.4Hz, 1H), 6.94 (dd, J=10.3, 2.3 Hz, 1H), 6.42 (s, 1H), 3.93 (s, 3H),2.91-2.85 (m, 1H), 1.02 (d, J=7.1 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H). ¹³CNMR (150 MHz, Acetone) δ 162.1, 160.6 and 159.1, 156.1, 138.7, 137.1 and137.0, 131.9, 129.2, 128.4, 127.0, 126.74 and 126.71, 125.9, 125.4,124.2, 120.3, 111.6, 110.3 and 110.1, 102.2, 98.3 and 98.1, 56.4, 26.9,24.3, 22.9. HRMS, calcd for C₂₃H₂₀ClFN₂O₃[M+H]⁺ m/z 427.1219, found427.1220.

Example 4. Synthesis of5-(6-fluoro-1H-indol-4-yl)-4-Isopropyl-3-(6-methoxy-1-(2-(thiazole-2-carboxamido)ethyl)-1H-indol-4-yl)-1H-pyrrole-2-carboxylicacid (177)

tert-Butyl (2-(4-bromo-6-methoxy-1H-indol-1-yl)ethyl)carbamate (177-3)

4-bromo-6-methoxy-1H-indole (177-1) (360 mg, 1.6 mmol) was dissolved inDMF and cooled to 0° C. NaH (60%, 128 mg, 3.2 mmol) was then added inportions followed by the addition of tert-butyl (2-bromoethyl)carbamate(177-2) (428 mg, 1.9 mmol). The mixture was allowed warm to r.t. andstirred for 12 h, then poured into water and extracted with EA. Theorganic phase was separated and washed with sat. aq. NaCl, dried overNa₂SO₄, filtered, concentrated and purified by flash chromatography toafford the title compound (380 mg yield 65%). ¹H NMR (600 MHz,Chloroform-d) δ 7.26 (s, 1H), 7.00 (t, J=2.4 Hz, 2H), 6.47 (d, J=3.2 Hz,1H), 4.52 (s, 1H), 4.19 (t, J=6.0 Hz, 2H), 3.85 (s, 3H), 3.47 (q, J=6.1Hz, 2H), 1.43 (s, 9H).

tert-Butyl(2-(6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethyl)carbamate(177-4)

In a sealed tube was combined tert-Butyl(2-(4-bromo-6-methoxy-1H-indol-1-yl)ethyl)carbamate (177-3) (380 mg, 1mmol), potassium acetate (303 mg, 3 mmol), bis(pinacolato)diboron (314mg, 1.2 mmol), and Pd(dppf)Cl₂ (25 mg, 0.03 mmol) followed by anhydrous1,4-dioxane (20 mL). The reaction mixture was stirred at 80° C. for 18 hand then cooled to room temperature. After dilution with ethyl acetate(15 mL) and filtration through a pad of celite, the filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography to provide 177-4 as a white solid (310 mg, 72%). ¹H NMR(600 MHz, Chloroform-d) δ 7.29 (t, J=1.8 Hz, 1H), 7.01 (d, J=2.6 Hz,1H), 6.99-6.89 (m, 2H), 4.53 (s, 1H), 4.20 (t, J=6.0 Hz, 2H), 3.88 (s,3H), 3.53-3.39 (m, 2H), 1.43 (d, J=1.7 Hz, 9H), 1.38 (s, 12H).

Methyl3-(1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-methoxy-1H-indol-4-yl)-5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(177-5)

Compound tert-Butyl(2-(6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethyl)carbamate(310 mg, 0.74 mmol), 57-7 (397 mg, 0.74 mmol), Pd(dppf)Cl₂ (60 mg, 0.074mmol) and Cs₂CO₃ (723 mg, 2.22 mmol) were dissolved in mixture ofTHF/H₂O (9/1, 10 mL). The resulting solution was degassed with argon.The mixture is then placed in a pre-heated oil bath at 80° C. for 12 hunder argon atmosphere, resulting in a black slurry. The mixture wascooled to room temperature, diluted with EtOAc (5 mL) and filteredthrough a Celite® plug eluting with additional ethyl acetate (2×3 mL).The resulting solution was washed with 1M of HCl (3×10 mL), saturatedaqueous NaHCO₃ solution (3×10 mL) and brine (10 mL). The organic layerwas dried over Na₂SO₄, filtered and evaporated in vacuo, the residue waspurified with column chromatograph to give a white solid 177-5. (190 mg,yield 34%). MS(ESI⁺), [M-t-Bu+1]⁺ 687.

Methyl5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-3-(6-methoxy-1-(2-(thiazole-2-carboxamido)ethyl)-1H-indol-4-yl)-1H-pyrrole-2-carboxylate(177-7)

To a DCM (5 mL) solution of compound Methyl3-(1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-methoxy-1H-indol-4-yl)-5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(177-5) (60 mg, 0.08) was added TFA (1 mL) at r.t, and the mixture wasstirred for 1 h, then the solvent and excess TFA was evaporated invacuo, the resulting residue was then dissolved in DCM (10 mL), andthiazole-2-carboxylic acid (177-6) (10 mg, 0.08 mmol) was added at 0° C.Then HATU (91 mg, 0.24 mmol) and DIPEA (0.09 mL, 0.48 mmol) was addedsuccessively. Then the mixture was stirred at r.t. for 2 h. Then sat.aq. NH₄Cl was added, the organic phase was separated and dried overNa₂SO₄, filtered and subject to flash chromatography to afforded the177-7. MS(ESI⁺), [M−1]⁺ 754.

5-(6-Fluoro-1H-indol-4-yl)-4-Isopropyl-3-(6-methoxy-1-(2-(thiazole-2-carboxamido)ethyl)-1H-indol-4-yl)-1H-pyrrole-2-carboxylicacid (177)

To a solution of methyl5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-3-(6-methoxy-1-(2-(thiazole-2-carboxamido)ethyl)-1H-indol-4-yl)-1H-pyrrole-2-carboxylate(177-7) (30 mg, 0.04 mmol) in methanol (2 mL), THF (2 ml) and water (1mL) was added 5 M NaOH (0.08 mL, 10 eq). The mixture was refluxed for 4h. The solvent is evaporated on a rotary evaporator to remove methanoland the solution is acidified with 1 M hydrochloric acid to give a whiteprecipitate with some slight foam. The solid is filtered and washed withwater (2 mL). Finally, the solid was further purified with columnchromatograph to obtain 177 as a white solid. 2.5 mg, yield 11%. ¹H NMR(600 MHz, Acetone-d₆) δ 10.47 (s, 2H), 8.25 (d, J=5.8 Hz, 1H), 7.93 (d,J=3.1 Hz, 1H), 7.90 (d, J=3.1 Hz, 1H), 7.41 (dd, J=3.2, 2.3 Hz, 1H),7.26 (ddd, J=9.7, 2.3, 0.9 Hz, 1H), 7.16-7.10 (m, 2H), 6.99 (dd, J=10.3,2.3 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 6.47 (ddd, J=3.1, 2.0, 0.9 Hz, 1H),6.18 (dd, J=3.2, 0.8 Hz, 1H), 4.47 (t, J=6.8 Hz, 2H), 3.90 (q, J=7.4 Hz,2H), 3.86 (s, 3H), 2.93-2.87 (m, 1H), 1.00 (d, J=7.1 Hz, 3H), 0.87 (d,J=7.1 Hz, 3H). ¹³C NMR (151 MHz, Acetone) δ 163.9, 161.2, 159.7, 158.2,156.0, 143.7, 136.7, 136.2, 136.1, 130.8, 130.0, 129.2, 128.7, 126.6,126.5, 126.2, 125.8, 125.7, 125.2, 124.9, 124.2, 119.4, 111.9, 109.6,109.5, 101.5, 101.5, 97.3, 97.1, 91.8, 54.8, 45.0, 39.5, 26.0, 23.1,23.0. HRMS, calcd for C₃₁H₂₈FN₅O₄S [M+H]⁺ m/z 586.1919, found 586.1917.

Example 5. Synthesis of3-(5-chloro-1H-indol-4-yl)-5-(1H-indol-6-yl)-4-isopropyl-1H-pyrrole-2-carboxylicacid (182)

In a sealed tube was combined 6-bromo-1H-indole (182-1) (400 mg, 2mmol), potassium acetate (589 mg, 6 mmol), bis(pinacolato)diboron (609mg, 2.4 mmol), and Pd(dppf)Cl₂ (49 mg, 0.06 mmol) followed by anhydrous1,4-dioxane (20 mL). The reaction mixture was stirred at 90° C. for 18 hand then cooled to room temperature. After dilution with ethyl acetate(15 mL) and filtration through a pad of celite, the filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography to provide6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole as a whitesolid (300 mg, 62%). MS(ESI⁺), [M+H]⁺ m/z 244.

Ethyl 5-bromo-1H-pyrrole-2-carboxylate 1-7 (50 mg, 0.09 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (44 mg, 0.18mmol), Pd(dppf)Cl₂ (7 mg, 0.009 mmol) and Cs₂CO₃ (59 mg, 0.18 mmol) weredissolved in mixture of THF/H₂O (9/1, 10 mL). The resulting solution wasdegassed with argon. The mixture is then placed in a pre-heated oil bathat 80° C. for 12 h under argon atmosphere, resulting in a black slurry.The mixture was cooled to room temperature, diluted with EtOAc (5 mL)and filtered through a Celite® plug eluting with additional ethylacetate (2×3 mL). The resulting solution was washed with 1M of HCl (3×10mL), saturated aqueous NaHCO₃ solution (3×10 mL) and brine (10 mL). Theorganic layer was dried over Na₂SO₄, filtered and evaporated in vacuo,the residue was purified with column chromatograph to give a white solidethyl3-(5-chloro-1-tosyl-1H-indol-4-yl)-5-(1H-indol-6-yl)-4-isopropyl-1H-pyrrole-2-carboxylate.(40 mg, yield 74%). MS(ESI⁺), [M+H]⁺ m/z 600.

To a solution of3-(5-chloro-1-tosyl-1H-indol-4-yl)-5-(1H-indol-6-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(40 mg, 0.006 mmol) in methanol (2 mL), THF (2 ml) and water (1 mL) wasadded 5 M NaOH (0.13 mL, 10 eq). The mixture was refluxed for 4 h. Thesolvent is evaporated on a rotary evaporator to remove methanol and thesolution is acidified with 1 M hydrochloric acid to give a whiteprecipitate with some slight foam. The solid is filtered and washed withwater (2 mL). Finally, the solid was further purified with columnchromatograph to obtain 182 as a white solid. Yield 36%. ¹H NMR (600MHz, Methanol-d₄) δ 7.52 (dd, J=8.1, 0.7 Hz, 1H), 7.47 (s, 1H),7.24-7.17 (m, 2H), 7.11 (dd, J=8.1, 1.5 Hz, 1H), 7.08 (d, J=3.1 Hz, 1H),7.06 (d, J=8.6 Hz, 1H), 6.39 (dd, J=3.1, 1.0 Hz, 1H), 6.02 (dd, J=3.1,0.9 Hz, 1H), 2.84-2.75 (m, 1H), 0.85 (d, J=7.1 Hz, 3H), 0.81 (d, J=7.1Hz, 3H). ¹³C NMR (151 MHz, MeOD) δ 163.0, 136.1, 135.3, 134.4, 130.5,127.8, 127.7, 127.6, 127.3, 126.5, 125.1, 124.8, 124.7, 121.7, 120.6,119.5, 118.2, 111.9, 110.6, 102.0, 101.0, 25.9, 22.8, 21.7. HRMS, calcdfor C₂₄H₂₀ClN₃O₂[M+H]⁺ m/z 418.1317, found 418.1315.

Example 6. Synthesis of5-(6-fluoro-1H-indol-4-yl)-3-(1H-indol-3-yl)-4-isopropyl-1H-pyrrole-2-carboxylicacid (203)

Methyl3-bromo-5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-Isopropyl-1H-pyrrole-2-carboxylate(203-1)

An oven-dried 10 mL Schlenk flask was charged with methyl3-bromo-5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(57-7) (267 mg, 0.5 mmol), Pd₂(dba)₃ (5 mg, 0.005 mmol) and XPhos (9.5mg, 0.02 mmol). The flask was evacuated and refilled with argon threetimes. Toluene (10 mL), triethylamine (151 mg, 1.5 mmol) andpinacolborane (142 mg, 1.5 mmol) were added and the flask was equippedwith a reflux condenser. The reaction mixture was heated at 110° C. for3 h. After cooling to RT, the reaction was quenched with water andextracted with EtOAc. The combined organic extracts were dried withNa₂SO₄ and solvent was removed in vacuo. Purification on silica gelcolumn chromatography afforded 203-1 as a white solid (180 mg, yield62%). MS(ESI⁺), [M+H]⁺ m/z 581. ¹H NMR (600 MHz, Acetone-d₆) δ 10.79 (s,1H), 7.99 (d, J=8.4 Hz, 2H), 7.80 (dd, J=9.7, 2.3 Hz, 1H), 7.78 (d,J=3.8 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.06 (dd, J=10.0, 2.3 Hz, 1H),6.65 (d, J=3.7 Hz, 1H), 3.79 (s, 3H), 2.90-2.81 (m, 1H), 2.41 (s, 3H),1.42 (s, 12H), 1.20 (d, J=7.1 Hz, 6H). ¹³C NMR (151 MHz, Acetone) δ161.0, 160.9, 159.4, 146.0, 135.0, 134.7, 130.3, 127.2, 127.1, 126.5,113.0, 112.8, 108.1, 100.1, 99.9, 83.3, 73.9, 50.4, 26.3, 24.7, 23.7,20.6.

Methyl5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-3-(1-tosyl-1H-indol-3-yl)-1H-pyrrole-2-carboxylate(203-3)

An oven-dried 10 mL flask was charged with 3-bromo-1-tosyl-1H-indole(203-2) (284 mg, 0.81 mmol), methyl3-bromo-5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylate(203-1) (470 mg, 0.81 mmol), K₃PO₄ (516 mg, 2.43 mmol), Pd₂(dba)₃ (1 mol%) and XPhos (4 mol %). The flask was evacuated and refilled with argonthree times. Dioxane and degassed water were added and the flask wasequipped with a reflux condenser. The reaction mixture was heated atreflux overnight. Purification on silica gel column chromatographyafforded the desired coupling product (280 mg, yield 48%). MS(ESI⁺),[M+H]⁺ m/z 724. ¹H NMR (600 MHz, Acetone-d₆) δ 11.03 (s, 1H), 8.09 (d,J=8.3 Hz, 1H), 8.06-7.98 (m, 4H), 7.84 (dd, J=9.7, 2.3 Hz, 1H), 7.80 (d,J=3.7 Hz, 1H), 7.71-7.66 (m, 1H), 7.63 (s, 1H), 7.60 (dd, J=8.5, 7.3 Hz,2H), 7.48 (d, J=8.3 Hz, 2H), 7.37 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.30(dt, J=7.7, 1.0 Hz, 1H), 7.27-7.22 (m, 1H), 7.17 (dd, J=9.9, 2.3 Hz,1H), 6.69 (dd, J=3.8, 0.8 Hz, 1H), 3.36 (d, J=1.1 Hz, 3H), 2.76-2.68 (m,1H), 0.96 (d, J=7.1 Hz, 3H), 0.75 (d, J=7.1 Hz, 3H).

3-(2-Chloro-3-methoxyphenyl)-5-(6-fluoro-1H-indol-4-yl)-4-isopropyl-1H-pyrrole-2-carboxylicacid (203)

To a solution of methyl5-(6-fluoro-1-tosyl-1H-indol-4-yl)-4-isopropyl-3-(1-tosyl-1H-indol-3-yl)-1H-pyrrole-2-carboxylate(203-3) (280 mg, 0.39 mmol) in methanol (5 mL), THF (5 ml) and water (2mL) was added 5 M NaOH (0.78 mL, 10 eq). The mixture was refluxed for 4h. The solvent is evaporated on a rotary evaporator to remove methanoland the solution is acidified with 1 M hydrochloric acid to give a whiteprecipitate with some slight foam. The solid is filtered and washed withwater (2 mL). Finally, the solid was further purified with columnchromatograph to obtain 203 as a white solid. Yield 59%. ¹H NMR (600MHz, Acetone-d₆) δ 10.48 (s, 1H), 10.47 (s, 1H), 10.27 (s, 1H), 7.46(dt, J=8.2, 0.9 Hz, 1H), 7.45-7.41 (m, 2H), 7.37-7.34 (m, 1H), 7.26 (dd,J=9.7, 2.3 Hz, 1H), 7.13 (t, J=8.2, 6.9 Hz, 1H), 7.04 (t, J=7.9, 7.0 Hz,1H), 6.99 (dd, J=10.4, 2.3 Hz, 1H), 6.49 (ddd, J=3.1, 2.0, 0.9 Hz, 1H),3.06-2.95 (m, 1H), 1.08 (d, J=7.1 Hz, 3H), 0.93 (d, J=6.7 Hz, 3H). ¹³CNMR (151 MHz, Acetone) δ 161.3, 159.7, 158.2, 136.4, 131.1, 131.1,130.4, 129.1, 126.6, 126.5, 125.8, 125.7, 125.1, 124.6, 124.4, 122.7,121.0, 120.6, 119.8, 118.8, 111.2, 110.1, 109.6, 109.4, 101.5, 97.3,97.1, 25.9, 23.3, 22.8. HRMS, calcd for C₂₄H₂₀FN₃O₂ [M+H]⁺ m/z 402.1612,found 402.1617.

TABLE A Exemplary compounds COMPOUND MW MW NUMBER STRUCTURE CALC [HRMS]Compounds with K_(D) < 20 μM 1

418.1317 418.1313 2

384.1707 3

454.1164 4

440.1008 5

424.1422 6

418.1317 7

432.1473 432.1470 8

432.1473 432.1470 9

446.1630 446.1634 10

486.1191 486.1192 11

448.1422 448.1426 12

434.1266 434.1266 13

452.0927 452.0926 14

436.1223 436.1226 15

439.0652 439.0650 16

404.1158 404.1160 17

379.1208 379.1205 18

434.1266 19

409.1313 409.1311 20

370.1550 370.1552 21

398.1863 398.1855 22

384.1707 384.1707 23

409.1313 409.1317 24

395.1157 395.1160 25

370.1550 370.1545 26

432.1473 432.1472 27

462.1579 462.1575 28

480.1485 480.1483 29

382.1550 382.1548 30

420.1518 420.1514 31

400.1656 400.1654 32

402.1612 402.1609 33

384.1707 384.1704 34

398.1863 398.1867 35

402.1612 402.1609 36

420.1518 420.1515 37

432.1718 432.1720 38

402.1612 402.1614 39

432.1718 432.1716 40

403.1565 403.1567 41

436.1223 436.1224 42

446.1874 446.1871 43

470.1486 470.1482 44

446.1874 446.1873 45

430.1925 430.1924 46

490.1773 490.1771 47

446.1511 446.1508 48

486.1435 486.1436 49

462.1215 462.1212 50

476.1616 476.1614 51

416.1769 416.1770 52

448.1422 448.1419 53

480.1121 480.1120 54

528.1541 528.1542 55

502.2137 502.2139 56

427.1219 427.1220 57

427.1219 427.1220 58

411.1515 411.1517 59

407.1765 407.1767 60

471.1118 471.1117 61

421.1558 421.1558 62

462.1282 462.1284 63

456.1718 456.1718 64

462.1282 462.1284 65

365.1057 365.1063 66

67

68

69

70

71

72

73

74

75

76

165

553.2609 553.2606 166

460.2031 460.2032 167

565.2012 565.2016 168

398.1863 398.1866 169

403.1565 403.1568 170

419.1269 419.1272 171

446.1874 446.1872 172

420.1177 420.1178 173

458.1874 458.1875 174

446.1874 446.1871 175

489.1933 489.1931 176

561.2508 561.2509 177

586.1919 586.1917 178

600.2075 600.2072 179

600.2075 600.2075 180

545.2559 545.2559 181

418.1317 418.1314 182

418.1317 418.1315 183

446.1874 446.1875 184

446.1630 446.1630 185

436.1223 436.1221 186

460.2031 460.2031 187

446.1874 446.1871 188

472.2395 472.2397 189

432.1718 432.1720 190

445.1670 445.1670 191

445.1670 445.1673 192

462.1824 462.1826 193

446.1874 446.1874 194

470.1735 470.1736 195

476.1980 476.1976 196

488.2344 488.2346 197

446.1511 446.1512 198

499.2140 499.2142 199

499.2140 499.2144 200

542.1657 542.1657 201

501.1391 501.1393 202

458.2238 458.2243 203

402.1612 402.1617 204

420.1177 205

403.13 206

402.15 207

417.1721 208

417.1721 209

417.1721 210

452.1769 211

470.1874 212

442.1925 213

444.1718 214

399.1816 215

416.1769 216

430.1925 217

436.14 218

435.14 219

450.15 220

449.16 221

464.17 222

399.1816 223

399.1816 224

485.1442 225

468.16 226

484.15 227

480.13 228

479.13 229

494.14 230

493.15 231

508.16 232

512.10 233

485.1395 234

485.21 235

471.20 236

473.18 237

445.18 238

461.16 239

444.20 240

444.20 241

416.1769 242

430.1925 243

420.1518 244

432.1718 245

437.1175 246

421.1471 247

433.1670 248

471.1439 249

469.1783 250

485.1442 251

479.1878 252

509.1983 253

513.1488 254

513.1488 255

484.2143 256

562.1919 257

591.2184 258

468.1830 259

478.1925 260

521.1983 261

528.1500 262

542.1657 263

494.14 264

493.15 265

522.17 266

508.16 267

507.16 268

269

270

428.1769 271

442.1925 272

442.1925 273

478.1231 274

442.1561 COMPOUNDS with K_(D) 20-50 μM 77

414.1812 414.1811 78

351.2067 351.2066 79

345.1598 345.1592 80

380.1160 81

410.0902 82

399.1320 399.1310 83

345.1603 345.1602 84

399.0667 399.0663 85

361.1547 86

349.1347 87

361.1552 361.1555 88

379.1213 379.1205 89

331.1447 331.1447 Compounds with K_(D) 50-100 μM 90

359.1754 359.1753 91

396.1109 92

381.1000 381.1008 93

351.0895 94

366.1004 95

379.1213 379.1207 96

407.1760 407.1761 97

423.1709 423.1707 98

361.1552 361.1555 99

345.1603 345.1607 100

345.1603 345.1604 101

345.1598 Compounds with K_(D) > 100 μM 102

337.1911 337.1906 103

439.1419 439.1424 104

416.1259 105

346.1550 106

407.1754 107

342.0897 342.0889 108

375.1709 375.1704 109

377.1665 377.1670 110

295.1441 111

297.1508 112

283.1447 283.1440 113

331.1441 331.1447 114

115

281.1290 281.1288 116

117

118

119

120

241.0977 241.0972 121

241.0977 241.0973 122

123

241.0977 241.0972 124

125

126

228.0773 228.0772 127

241.0977 241.0974 128

129

130

204.0661 204.0656 131

132

133

134

227.0821 227.0816 135

136

137

138

139

140

141

142

143

144

145

226.0980 226.0979 146

271.1083 271.1077 147

203.0821 203.0817 148

149

150

151

152

153

154

155

156

157

158

159

160

239.0821 239.0819 161

365.1665 365.1659 162

393.1370 393.1370 163

164

A compound of any one of Formulas (I), (II), and (III) may be selectedfrom compounds listed in Table A. Compounds of Formula (I), (II), or(III) that are not listed in Table A are also within the scope herein.In some embodiments, compounds of Formula (I), (II), and (III) maycomprise any of the substituents depicted in the compounds of Table A,in any suitable combinations.

REFERENCES

The following references are herein incorporated by reference in theirentireties.

-   1. Dick, J. E., Stem cell concepts renew cancer research.    Blood, 2008. 112(13): p. 4793-807.-   2. Zhou, B. B., H. Zhang, M. Damelin, K. G. Geles, J. C. Grindley,    and P. B. Dirks, Tumour-initiating cells: challenges and    opportunities for anticancer drug discovery. Nat Rev Drug    Discov, 2009. 8(10): p. 806-23.-   3. Shlush, L. I., S. Zandi, A. Mitchell, W. C. Chen, J. M.    Brandwein, V. Gupta, J. A. Kennedy, A. D. Schimmer, A. C.    Schuh, K. W. Yee, J. L. McLeod, M. Doedens, J. J. Medeiros, R.    Marke, H. J. Kim, K. Lee, J. D. McPherson, T. J. Hudson, H.    P.-L. G. P. Consortium, A. M. Brown, F. Yousif, Q. M. Trinh, L. D.    Stein, M. D. Minden, J. C. Wang, and J. E. Dick, Identification of    pre-leukaemic haematopoietic stem cells in acute leukaemia.    Nature, 2014. 506(7488): p. 328-33.-   4. Martin-Perez, D., M. A. Piris, and M. Sanchez-Beato, Polycomb    proteins in hematologic malignancies. Blood, 2010. 116(25): p.    5465-75.-   5. Sauvageau, M. and G. Sauvageau, Polycomb group proteins:    multi-faceted regulators of somatic stem cells and cancer. Cell Stem    Cell, 2010. 7(3): p. 299-313.-   6. Radulovic, V., G. de Haan, and K. Klauke, Polycomb-group proteins    in hematopoietic stem cell regulation and hematopoietic neoplasms.    Leukemia, 2013. 27(3): p. 523-33.-   7. Cao, L., J. Bombard, K. Cintron, J. Sheedy, M. L. Weetall,    and T. W. Davis, BMI1 as a novel target for drug discovery in    cancer. J Cell Biochem, 2011. 112(10): p. 2729-41.-   8. Gieni, R. S. and M. J. Hendzel, Polycomb group protein gene    silencing, non-coding RNA, stem cells, and cancer. Biochem Cell    Biol, 2009. 87(5): p. 711-46.-   9. Wang, H., L. Wang, H. Erdjument-Bromage, M. Vidal, P.    Tempst, R. S. Jones, and Y. Zhang, Role of histone H2A    ubiquitination in Polycomb silencing. Nature, 2004. 431(7010): p.    873-8.-   10. Cao, R., Y. Tsukada, and Y. Zhang, Role of Bmi-1 and Ring1A in    H2A ubiquitylation and Hox gene silencing. Mol Cell, 2005. 20(6): p.    845-54.-   11. Haupt, Y., W. S. Alexander, G. Barri, S. P. Klinken, and J. M.    Adams, Novel zinc finger gene implicated as myc collaborator by    retrovirally accelerated lymphomagenesis in E mu-myc transgenic    mice. Cell, 1991. 65(5): p. 753-63.-   12. Lessard, J. and G. Sauvageau, Bmi-1 determines the proliferative    capacity of normal and leukaemic stem cells. Nature, 2003.    423(6937): p. 255-60.-   13. Liu, L., L. G. Andrews, and T. O. Tollefsbol, Loss of the human    polycomb group protein BMI1 promotes cancer-specific cell death.    Oncogene, 2006. 25(31): p. 4370-5.-   14. Rizo, A., S. Olthof, L. Han, E. Vellenga, G. de Haan, and J. J.    Schuringa, Repression of BMI in normal and leukemic human CD34(+)    cells impairs self-renewal and induces apoptosis. Blood, 2009.    114(8): p. 1498-505.-   15. Jagani, Z., D. Wiederschain, A. Loo, D. He, R. Mosher, P.    Fordjour, J. Monahan, M. Morrissey, Y. M. Yao, C. Lengauer, M.    Warmuth, W. R. Sellers, and M. Dorsch, The Polycomb group protein    Bmi-1 is essential for the growth of multiple myeloma cells. Cancer    Res, 2010. 70(13): p. 5528-38.-   16. Xu, Z., H. Liu, X. Lv, Y. Liu, S. Li, and H. Li, Knockdown of    the Bmi-1 oncogene inhibits cell proliferation and induces cell    apoptosis and is involved in the decrease of Akt phosphorylation in    the human breast carcinoma cell line MCF-7. Oncol Rep, 2011.    25(2): p. 409-18.-   17. Meng, X., Y. Wang, X. Zheng, C. Liu, B. Su, H. Nie, B. Zhao, X.    Zhao, and H. Yang, shRNA-mediated knockdown of Bmi-1 inhibit lung    adenocarcinoma cell migration and metastasis. Lung Cancer, 2012.    77(1): p. 24-30.-   18. Liang, W., D. Zhu, X. Cui, J. Su, H. Liu, J. Han, F. Zhao,    and W. Xie, Knockdown BMI1 expression inhibits proliferation and    invasion in human bladder cancer T24 cells. Mol Cell Biochem, 2013.    382(1-2): p. 283-91.-   19. Ruan, Z. P., R. Xu, Y. Lv, T. Tian, W. J. Wang, H. Guo,    and K. J. Nan, Bmi1 knockdown inhibits hepatocarcinogenesis. Int J    Oncol, 2013. 42(1): p. 261-8.-   20. Li, Z., R. Cao, M. Wang, M. P. Myers, Y. Zhang, and R. M. Xu,    Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex.    J Biol Chem, 2006. 281(29): p. 20643-9.-   21. Wei, J., L. Zhai, J. Xu, and H. Wang, Role of Bmi1 in H2A    ubiquitylation and Hox gene silencing. J Biol Chem, 2006.    281(32): p. 22537-44.-   22. Warner, J. K., J. C. Wang, K. Takenaka, S. Doulatov, J. L.    McKenzie, L. Harrington, and J. E. Dick, Direct evidence for    cooperating genetic events in the leukemic transformation of normal    human hematopoietic cells. Leukemia, 2005. 19(10): p. 1794-805.-   23. Barabe, F., J. A. Kennedy, K. J. Hope, and J. E. Dick, Modeling    the initiation and progression of human acute leukemia in mice.    Science, 2007. 316(5824): p. 600-4.

The invention claimed is:
 1. A polycomb repressive complex 1 (PRC1)inhibitor of Formula (II):

wherein A is a 5 or 6-member aryl or heteroaryl ring, A′ is a 5-memberheteroaryl ring, E is a 5 or 6-member aryl or heteroaryl ring, and E′ isabsent or is a 5-member or heteroaryl ring; wherein R² is a straight,branched, or cyclic alkyl group of 1-6 carbons and comprising 0-3halogen atoms or OH; wherein R⁴ is a (CH₂)₀₋₅COOH, (CH₂)₀₋₆OH,tetrazole, —(CH₂)₀₋₅C(O)NH₂, —(CH₂)₀₋₅C(O)NH(CH₂)₀₋₃, C(O)O(CH₂)₁₋₅,—(CH₂)₀₋₅SO₂NH₂, —(CH₂)₀₋₅SO₂CH₃, or —NHSO₂NH₂—, wherein X is, NH, NR⁵,O, or S; wherein R⁵, when present, is CH₃, (CH₂)₁₋₅CH₃, (CH₂)₁₋₆—COOH,(CH₂)₁₋₆—CONH₂, (CH₂)₁₋₆—SO₂NH₂, (CH₂)₁₋₆—OH, or NH₂; and whereinR^(A1-5), R^(A′1-5), R^(E1-5), and R^(E′1-5) may be absent or present,may be located at any position on A, A′, E, E′, respectively, and whenpresent is selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, —OCF₃, —OH,—O(CH₂)₁₋₅, CH₂OH, (CH₂)₀₋₃OH, (CH₂)₁₋₅O(CH₂)₁₋₅CH₃, —OR⁶, OCH₃,O(CH₂)₁₋₃CH3, (CH₂)₀₋₂CONH₂, O(CH₂)₁₋₄COOH, —(CH₂)₀₋₅NHCOR⁶,—(CH₂)₀₋₅CONHR⁶, —NH₂, (CH₂)₀₋₂NH₂, —(CH₂)₀₋₆SR⁶, —(CH₂)₀₋₄COOH,—(CH₂)₀₋₃SO₂NH₂, —(CH₂)₀₋₃SO₂CH3, —NHSO₂NH₂, —NHSO₂CH₃, —SH, —CN, —NO₂,halogen, a 5- or 6-member heteroaryl ring, a 5-6 member cycloalkylheteroalkyl ring, —CH₂-cyclobuthyl, and —(CH₂)₀₋₃—S(CH₂)₀₋₃; wherein R⁶,when present, is C₁-C₆ alkyl, C₁-C₅ haloalkyl, —(CH₂)₁₋₆OH,—(CH₂)₁₋₆COOH, —(CH₂)₁₋₅O(CH₂)₁₋₅CH₃, —(CH₂)₁₋₆CONH₂, a 5- or 6-memberheteroaryl ring, or a 5-6 member cycloalkyl or heteroalkyl ring.
 2. APRC1 inhibitor comprising a compound selected from:


3. A pharmaceutical composition comprising the PRC1 inhibitor of claim 1and a pharmaceutically acceptable carrier.
 4. The pharmaceuticalcomposition of claim 3, wherein the pharmaceutical composition isformulated for oral administration.
 5. The pharmaceutical composition ofclaim 3, wherein the pharmaceutical composition is formulated forinjection.
 6. A method of inhibiting PRC1 with an effective amount of apharmaceutical composition of claim
 3. 7. The method of claim 6, whereinPRC1 activity is inhibited by binding of the compound or pharmaceuticalcomposition to PRC1.
 8. A method of treating a subject comprisingadministering to the subject a pharmaceutical composition of claim
 3. 9.The method of claim 8, wherein the subject suffers from cancer.
 10. Themethod of claim 9, wherein the cancer comprises leukemia, hematologicmalignancy, solid tumor cancer, breast cancer, prostate cancer, coloncancer, pancreatic cancer, ovarian cancer, liver cancer or thyroidcancer.
 11. The method of claim 10, wherein the pharmaceuticalcomposition is co-administered with an additional therapeutic.
 12. Themethod of claim 11, wherein the subject is a human.
 13. The PRC1inhibitor of claim 1, wherein the compound is selected from: